System and methods for diagnosis and treatment of discogenic lower back pain

ABSTRACT

Methods and devices to treat discogenic lumbar back pain are disclosed. Electrodes are implanted within the anterior epidural space of the patient. A pulse generator that is connected to the electrodes delivers electrical impulses to sympathetic nerves located within the posterior longitudinal ligament (PLL) of the lumbar spine and outer posterior annulus fibrosus of the intervertebral disc. In alternate embodiments, energy directed to nerves in the PLL may be from light or mechanical vibrations, or the nerves may be cooled. The electrodes may also be used diagnostically to correlate spontaneous nerve activity with spinal movement, fluctuations in autonomic tone and the patient&#39;s experience of pain. The electrodes may also be used to generate diagnostic evoked potentials. The diagnostic data are used to devise parameters for the therapeutic nerve stimulation. Automatic analysis of the data may be incorporated into a closed-loop system that performs the nerve stimulation automatically.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a division of application Serial Number U.S.Ser. No. 14/465,822 having publication No. US 20150005680 which wasfiled on Aug. 21, 2014 and which issued as U.S. Pat. No. 9,789,313 onOct. 17, 2017. That application is a continuation-in-part of applicationSerial Number U.S. Ser. No. 13/402,093 having publication No. US20120215218 which was filed Feb. 22, 2012 and which issued as U.S. Pat.No. 8,880,189 on Nov. 4, 2014. The present application also claims thebenefit of a division of that application Serial Number U.S. Ser. No.13/402,093, namely, Serial Number U.S. Ser. No. 14/099,910 havingpublication No. US 20140135876, which was filed 7 Dec. 2013 and whichissued as patent No. U.S. Pat. No. 8,892,215 on Nov. 18, 2014. Thosethree applications, as well as the present application, claim thebenefit of provisional patent application number U.S. 61/463,800,entitled System and Method for Electrical Stimulation of the LumbarVertebral Column, to J. D. LIPANI, with a filing date of Feb. 23, 2011.All of the applications that are cited above are herein incorporated byreference for all purposes.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses to bodily tissues for therapeutic purposes. The disclosedmethods and devices may be used to diagnose and/or treat discogeniclower back pain, by selectively stimulating or evaluating the functionof nerves that innervate a posterior longitudinal ligament and/or theadjacent outer posterior annulus fibrosus of a lumbar disc. In preferredembodiments of the invention, the delivered energy is in the form ofelectrical impulses, but the delivery of light, mechanical-vibration andthermal energy is also disclosed, as well as the removal of heat(cooling) from nerve tissue.

More specifically, the present invention is directed to methods anddevices for the treatment of chronic lower back pain that may resultfrom a degenerated or injured intervertebral disc, orparaspinal-mediated low back pain. Electrodes placed in an anteriorepidural space of the patient, along with a pulse generator that isconnected to the electrodes, are used to deliver electrical impulses tonociceptive and/or other nerves located within the posteriorlongitudinal ligament (PLL) of the lumbar spine and the superficiallayer of the dorsal aspect of the annulus fibrosus that lies under thePLL. Alternatively or in addition, devices that generate time-varyinglight, heat, cold, or mechanical vibration are applied to such nerves,and those devices are supplied with energy by corresponding signal(pulse) generators. According to the invention, these modalities ofstimulation in the lumbar region may reduce back pain in a patientreversibly, adjustably, and with almost complete coverage of thepain-generating region, for example, by interfering with or modulatingafferent pain signals to the brain that originate in those nerves.Alternatively, if the reversible stimulation is unsuccessful inalleviating the back pain, stimulation parameters may be selected so asto irreversibly damage the ability of the nerves to send pain signals tothe brain. Methods are also described for diagnosing thepathophysiological origin of the back pain, and those diagnostic methodsmay be used to select the stimulation parameters for the disclosedtherapeutic methods and devices, thereby individualizing treatment ofthe patient.

The disclosed methods involve the implantation of stimulation devices,such as electrodes, within the anterior epidural space, adjacent to theposterior longitudinal ligament (PLL) of the lumbar spine. Suchimplantation is disclosed in detail below, but for purposes of providingbackground information, the relevant anatomy of the spine and vertebraewill first be summarized and illustrated in FIGS. 1 to 4.

Proceeding from the neck to the tailbone, there are 7 cervical (neck)vertebrae (C1-C7), 12 thoracic vertebrae (T1-T12), and 5 lumbarvertebrae (L1-L5). This is followed by the 5 sacral and coccyx(tailbone) vertebrae, which are inserted like a wedge between the twohip bones. The present invention is concerned primarily with the lumbarvertebrae L3 to L5, although it is understood that the invention may beadapted for use in other vertebrae as well, for example, the lumbarvertebrae L1 to L3, or the sacral vertebrae.

The vertebral column comprises bony vertebral bodies that are separatedby cartilaginous intervertebral discs. A primary function of thevertebral column is to provide mechanical support for the body. Theintervertebral discs provide a cushion between the vertebral bodies,absorbing some of the axial load and also facilitating motion within thevertebral column. Each disc contains a soft gel-like center (the nucleuspulposus), which is constrained radially by an elastic outer band, theannulus fibrosus. Each vertebral body articulates with its neighboringvertebral body above and below, which allows for some degree of flexion,extension, and rotation [HUMZAH M D, Soames R W. Human intervertebraldisc: structure and function. Anat Rec 220(4, 1988):337-356].

Ligaments connect two or more bones and help stabilize joints. Thepresent invention is concerned particularly with the posteriorlongitudinal ligament (PLL), which runs axially along the interiorportion of the vertebral bodies and of the annulus fibrosus of the discsthat lie between the vertebral bodies. The PLL protects the discs andimparts stability during flexion of the body [David W. L Hukins andJudith R. Meakin. Relationship between structure and mechanical functionof the tissues of the intervertebral joint. Amer. Zool. 40(2000):42-52].Furthermore, nerves that innervate the PLL may participate in reflexloops that cause back muscles to stabilize the spine. Thus, neuralreceptors in the posterior longitudinal ligament, simultaneously withthe output of the receptors from other ligaments such as the supraspinalligament, as well as receptors in the discs, are thought to add theirneural outputs to spinal interneurons, so as to reflexively activate themultifidus and longissimus muscles of the back in order to stabilize thespine in response to loads and movements [PANJABI M M. Clinical spinalinstability and low back pain. J Electromyogr Kinesiol 13(4,2003):371-379].

The posterior longitudinal ligament may be injured (sprained, as astretch and/or tear) as the result of sudden violent contraction, suddentorsion, lifting a heavy object, or other acute mechanical events.Because the PLL lies adjacent to the posterior annulus fibrosus of theintervertebral disc, inflammation of the disc that results fromdegeneration or herniation of the disc may secondarily contribute todysfunction of the PLL, e.g., via inflammatory mediators. The mostthoroughly investigated disease of the PLL itself is its ossification,which is more common in the cervical (70%), as compared to eitherthoracic (15%) or lumbar (15%) regions [Joji INAMASU, Bernard H. Guiotand Donald C. Sachs. Ossification of the Posterior LongitudinalLigament: An Update on Its Biology, Epidemiology, and Natural History.Neurosurgery 58(6, 2006): 1027-1039]. The PLL may also fold and compressa nerve root [BEATTY R A, Sugar O, Fox T A. Protrusion of the posteriorlongitudinal ligament simulating herniated lumbar intervertebral disc. JNeurol Neurosurg Psychiatry 31(1, 1968):61-66].

Each vertebra is composed of the above-mentioned vertebral body(anteriorly) and an arch (posteriorly). Processes protrude from eacharch and serve as points of attachment for muscles of the back. Aspinous process protrudes backwards on each arch, and transverseprocesses extend from the lateral edges of each arch. The parts of thearch between the spinous and transverse processes are known as laminae,and the parts of the arch between the transverse processes and the bodyare known as pedicles. At the point where the laminae and pedicles meet,each vertebra contains two superior articular facets and two inferiorarticular facets. The pedicle of each vertebra is notched at itssuperior and inferior edges. Together the notches from two contiguousvertebrae form an opening, the intervertebral neural foramen, throughwhich spinal nerves pass.

A vertebral arch also contains an opening (the vertebral foramen) whichforms a canal through which the spinal cord passes, protecting thespinal cord and nerve roots that exit from it. Because the spinal cordstops growing in infancy while the bones of the spine continue to grow,the spinal cord in adults ends at about the level of the vertebra L1/L2.Below that vertebral level, a bundle-like structure of nerve fibers,known as the cauda equina, occupy the vertebral foramen, which emanatesfrom the terminus of the spinal cord (the conus medullaris). Thus, thelumbar vertebral foramen surrounds the spinal cord/conus medullarisabove vertebrae L1/L2 and the cauda equina nerve roots below vertebraeL1/L2. [J. D. STEWART Cauda equina disorders. Chapter 6, pp 63-74. In:Neurologic Bladder, Bowel and Sexual Dysfunction (Clare J Fowler et al,eds) Amsterdam: Elsevier Science, 2001].

The above-mentioned structures are illustrated in FIGS. 1 to 4. Featuresshown in those figures that are particularly relevant to the presentinvention include the location of the posterior longitudinal ligament(PLL) and the annulus fibrosus of the intervertebral disc(s) that liesadjacent to the PLL. For future reference, the location of stimulationdevices of the present invention, which are implanted adjacent to thePLL, is also shown in FIGS. 1-4 (item 6 in FIG. 1, item 6 in FIG. 2,item 6 in FIG. 3, and within regions 50 and/or 51 in FIG. 4).

FIG. 1 shows the spine in a cross section perpendicular to its longaxis, cut through one of the lumbar discs. The interconnections betweenthe nerves that are shown in FIG. 1 are relevant to the mechanism bywhich the disclosed stimulation of nerves innervating the PLL andannulus fibrosus may reduce back pain [EDGAR M A. The nerve supply ofthe lumbar intervertebral disc. J Bone Joint Surg Br 89(9,2007):1135-1139]. Structures labeled in FIG. 1 are as follows: nucleuspulposus 1; annulus fibrosus 2; anterior longitudinal ligament 3;posterior longitudinal ligament 4; thecal sac 5; devices (e.g.,electrodes) of the present invention situated in the anterior epiduralspace 6; filum terminale 7; intrathecal nerve root of the cauda equina8; ventral nerve root 9; dorsal nerve root 10; dorsal root ganglion 11;dorsal ramus of the spinal nerve 12; medial branch of the dorsal ramus13; sinuvertebral nerve (meningeal branch of the spinal nerve) 14;connecting sympathetic branch from gray ramus to sinuvertebral nerve 15;neural radicals from sinuvertebral nerve to disc 16; white ramuscommunicans 17; gray ramus communicans 18; sympathetic neural radicalsto disc surface 19; paraspinal sympathetic ganglion 20; paraspinalsympathetic chain 21; anterior branch from sympathetic ganglion to discsurface 22; branches from sympathetic ganglion to disc surface 23; andposterior epidural space 24. FIG. 1 is adapted from: J. Randy JINKINS.The anatomic and physiologic basis of local, referred, and radiatinglumbosacral pain syndromes related to disease of the spine. JNeuroradiol 31(2004): 163-180.

FIG. 2 shows a section of the spine viewed from the side(left-to-right). The section is angled slightly away from the midline ofthe back, so as to demonstrate many of the ligaments of the spine.Vertebral bodies are labeled T12 through S1 as shown. Structuresotherwise labeled in FIG. 2 are as follows: anterior longitudinalligament 3; posterior longitudinal ligament 4; spinal cord 26; caudaequina 27; membrane of dura mater that surrounds the spinal cord and thecauda equina (thecal sac, dural tube) containing cerebral spinal fluid5; devices (e.g., electrodes) of the present invention situated in theanterior epidural space 6; posterior epidural space 24; anteriorepidural space 25; intervertebral disc 29; ligamentum flavum 30;interspinous ligament 31; supraspinous ligament 32; sacrococcygealligament 33; and sacral hiatus 34.

FIG. 3 shows a posterior-to-anterior view of the lumbar spine, viewedobliquely on the left side of the patient. Vertebral bodies are labeledL3 through L5 as shown. The structures that are otherwise labeled inFIG. 3 are as follows: posterior longitudinal ligament 4; devices (e.g.,electrodes) of the present invention situated in anterior epidural space6; membrane of dura mater that surrounds the cauda equina (thecal sac,dural tube), containing cerebral spinal fluid 5; cauda equina nerveroots 27; intervertebral disc 29; ligamentum flavum 30; L3 nerve root35; L4 nerve root 36; L5 nerve root 37; pedicle (cut) 40; lamina (cut)41; spinous process 42; transverse process 43; superior articularprocess 44; and facet joint 45.

The present invention stimulates nerves in the PLL, in the connectivetissue between the PLL and annulus fibrosus and/or periosteum, and inthe superficial layer of the dorsal aspect of the annulus fibrosus thatlies under the PLL [BOGDUK N, Tynan W, Wilson A S. The nerve supply tothe human lumbar intervertebral discs. J Anat 132(1, 1981):39-56; EDGARM A. The nerve supply of the lumbar intervertebral disc. J Bone JointSurg Br 89(9, 2007):1135-1139; KOJIMA Y, Maeda T, Arai R, Shichikawa K.Nerve supply to the posterior longitudinal ligament and theintervertebral disc of the rat vertebral column as studied byacetylcholinesterase histochemistry. I. Distribution in the lumbarregion. J Anat 169(1990):237-246; J. H. MULLIGAN. The innervation of theligaments attached to the bodies of the vertebrae. J Anat 91(4, 1957):455-465]. FIG. 4 shows a posterior-to-anterior view of the innervationof the posterior longitudinal ligament (PLL) and of the annulus fibrosusof the intervertebral disc that lies adjacent to the PLL. In this view,many of the structures shown in FIG. 3 are removed. Structures labeledin FIG. 4 are as follows: posterior longitudinal ligament 4;intervertebral fibers of the PLL 48; vertebral (longitudinal) fibers ofthe PLL 49; sinuvertebral nerve 14; nerve root 38; pedicle (cut) 40;horizontal region that may be stimulated by the disclosed devices 50;and vertical (longitudinal) region that may be stimulated by thedisclosed devices 51.

Low back pain is extremely prevalent and is the second most commonreason for patients to seek medical attention. Pain may be elicitedduring times of overexertion that results in sprain, strain, or spasm inone or more of the muscles or ligaments in the back. If the spinebecomes overly strained or compressed, a disc may rupture or bulgeoutward. Prolonged stresses or degenerative changes facilitated bygenetic predisposition, aging, obesity, smoking, arthritis, poorposture, or unhealthy activity-related habits may result in injury tothe intervertebral disc, resulting in chronic discogenic-mediated lowback pain [Devon I RUBIN. Epidemiology and risk factors for spine pain.Neurol Clin 25(2007): 353-371; MANCHIKANTI L, Singh V, Datta S, Cohen SP, Hirsch J A; American Society of Interventional Pain Physicians.Comprehensive review of epidemiology, scope, and impact of spinal pain.Pain Physician 12(4, 2009):E35-E70].

Acute back pain tends to come on suddenly, but also tends to improve ina short period of time with short-term conservative treatment, such asmedication, exercise, physical therapy or rest [ATLAS S J, Deyo R A.Evaluating and managing acute low back pain in the primary care setting.J Gen Intern Med 16(2, 2001):120-131]. Chronic back pain is commonlydescribed as deep, aching, dull or burning pain in one area of the back,which may also travel down the leg(s). It tends to last a month or moreor may be a persistent unrelenting problem. Sciatica is pain that beginsin the hip and/or buttocks and travels down the back of the leg. Thereare many causes of chronic back pain, including some that are fromintra-abdominal disorders that can cause pain to be referred to theback. Other examples of causes of back pain are as follows: Aradiculopathy can be due to a pinched nerve resulting from a herniateddisc; sciatica can be due to pinched nerves in vertebrae L4-S3; centralspinal stenosis is due to narrowing of the spinal canal; foraminalstenosis is due to bone spurs that protrude into the neural foramen andput pressure on a nerve root; and low back pain can also be due togradual loss of normal spinal structure associated with spondylosis,spinal osteoarthritis, and/or degenerative disc disease [MichaelDEVEREAUX. Low back pain. Med Clin N America 93(2009):477-501; MichelleL I N. Musculoskeletal Back Pain. Chapter 51, pp 591-603. In: Rosen'sEmergency Medicine: Concepts and Clinical Practice, 7th edition (Marx JA, Hockberger R S, Walls R M, et al, eds). Philadelphia: Mosby Elsevier,2009; LAST A R, Hulbert K. Chronic low back pain: evaluation andmanagement. Am Fam Physician 79(12, 2009):1067-1074; McCAMEY K, Evans P.Low back pain. Prim Care 34(1, 2007):71-82]. CHOU et al provide aflowchart to assist in the diagnosis and subsequent treatment of lowback pain [CHOU R, Qaseem A, Snow V, Casey D, Cross J T Jr, Shekelle P,Owens D K; Clinical Efficacy Assessment Subcommittee of the AmericanCollege of Physicians; American College of Physicians; American PainSociety Low Back Pain Guidelines Panel. Diagnosis and treatment of lowback pain: a joint clinical practice guideline from the American Collegeof Physicians and the American Pain Society. Ann Intern Med 147(7,2007): 478-491].

The present invention is concerned primarily with back pain that is dueto degenerative disc disease, wherein degenerative changes followingloss of hydration of the nucleus pulposus lead to circumferential orradial tears within the annulus fibrosus. Annular tears within the outerannulus stimulate the ingrowth of blood vessels and accompanyingnociceptors into the outer annulus, for example, from the overlyingposterior longitudinal ligament. Nerve endings are recruited to the areaof injury and sensitized by inflammatory cytokines and otherchemofactors. Pain transmission is then sustained by chronicinflammation and exacerbated by constant axial loading [KALLEWAARD J W,Terheggen M A, Groen G J, Sluijter M E, Derby R, Kapural L, Mekhail N,van Kleef M. (15.) Discogenic low back pain. Pain Practice 10(6,2010):560-579; Keith D. WILLIAMS and Ashley L. Park. Lower Back Pain andDisorders of Intervertebral Discs. Chapter 39, pp. 2159-2236. In:Campbell's Operative Orthopaedics, 11th edition (S. Terry Canale andJames H. Beatty, eds). Philadelphia: Mosby Elsevier, 2007; AUDETTE J F,Emenike E, Meleger A L. Neuropathic low back pain. Curr Pain HeadacheRep 9(3, 2005):168-177; HURRI H, Karppinen J. Discogenic pain. Pain112(3, 2004):225-228; FREEMONT A J, Peacock T E, Goupille P, Hoyland JA, O'Brien J, Jayson M I. Nerve ingrowth into diseased intervertebraldisc in chronic back pain. Lancet 350(9072, 1997):178-181].

Although the pathophysiology of degenerative disc disease isincompletely understood, it is thought that sensitization of thesenociceptors by various inflammatory repair mechanisms may lead tochronic discogenic pain [MARTIN M D, Boxell C M, Malone D G.Pathophysiology of lumbar disc degeneration: a review of the literature.Neurosurg Focus 13(2, 2002):Article 1, pp. 1-6; PENG B, Wu W, Hou S, LiP, Zhang C, Yang Y. The pathogenesis of discogenic low back pain. J BoneJoint Surg Br 87(1, 2005): 62-67; Y. AOKI, K. Takahashi, S. Ohtori & H.Moriya: Neuropathology Of Discogenic Low Back Pain: A Review. TheInternet Journal of Spine Surgery 2 (1, 2005): 1-9; WALKER M H, AndersonD G. Molecular basis of intervertebral disc degeneration. Spine J 4(6Suppl, 2004):1585-1665; BOSWELL M V, et al. Interventional techniques:evidence-based practice guidelines in the management of chronic spinalpain. Pain Physician 10(1, 2007):7-111; J. Randy JINKINS. The anatomicand physiologic basis of local, referred, and radiating lumbosacral painsyndromes related to disease of the spine. J Neuroradiol 31(2004):163-180; SEAMAN D R, Cleveland C 3rd. Spinal pain syndromes:nociceptive, neuropathic, and psychologic mechanisms. J ManipulativePhysiol Ther 22(7, 1999):458-472; NAKAMURA S I, Takahashi K, TakahashiY, Yamagata M, Moriya H. The afferent pathways of discogenic low-backpain. Evaluation of L2 spinal nerve infiltration. J Bone Joint Surg Br78(4, 1996):606-612; TAKEBAYASHI T, Cavanaugh J M, Kallakuri S, Chen C,Yamashita T. Sympathetic afferent units from lumbar intervertebraldiscs. J Bone Joint Surg Br 88(4, 2006):554-557].

The current standard for diagnosing discogenic pain ispressure-controlled provocative discography [TOMECEK F J, Anthony C S,Boxell C, Warren J. Discography interpretation and techniques in thelumbar spine. Neurosurg Focus 13(2, 2002):Article 13, pp 1-8; ZHANG Y G,Guo T M, Guo X, Wu S X. Clinical diagnosis for discogenic low back pain.Int J Biol Sci 5(7, 2009):647-658]. With this procedure, needles areinserted through the back into the disc near the suspect area, guided byfluoroscopic imaging. Fluid is then injected to pressurize the disc, andany pain responses are recorded. The fluid may comprise a radiographiccontrast agent, thereby allowing disc morphology to be imaged, so thatthe procedure provides both anatomical and functional information abouta diseased disc. Diagnostic nerve blockade may also be used tocharacterize the nerve source of the low back pain [MANCHIKANTI L, SinghV, Pampati V, Damron K S, Barnhill R C, Beyer C, Cash K A. Evaluation ofthe relative contributions of various structures in chronic low backpain. Pain Physician 4(4, 2001):308-316]. However, interpretation ofresults given by provocative discography and nerve blockade can beequivocal or controversial, and those methods do not necessarily predictthe success of potential disc therapies. Accordingly, it is an objectiveof the present invention to provide improved diagnostic procedures thatmay complement results provided by discography and nerve blockade, andthat are also particularly well-suited for use in selecting parametersof the therapeutic nerve-stimulation procedures that are disclosed here.Thus, if a patient is a candidate for provocative discography or nerveblockade, the presently disclosed diagnostic methods may be performed inconjunction with those invasive procedures, or the disclosed methods maybe performed by themselves.

Several therapies have been used to target the nociceptive nerve fiberswithin the affected discs in patients with discogenic back pain.Non-surgical techniques involve pain medication and physical therapywith behavioral modification [KINKADE S. Evaluation and treatment ofacute low back pain. Am Fam Physician 75(8, 2007):1181-1188; Brian SWILLIAMS and Paul J Christo. Pharmacological and interventionaltreatments for neuropathic pain. Chapter 12, pp 295-375. In: Mechanismsof Pain in Peripheral Neuropathy (M Dobretsov and J-M Zhang, eds).Trivandrum, India: Research Signpost, 2009; CHOU R, Huffman L H;American Pain Society; American College of Physicians. Nonpharmacologictherapies for acute and chronic low back pain: a review of the evidencefor an American Pain Society/American College of Physicians clinicalpractice guideline. Ann Intern Med 147(7, 2007): 492-504].

Other destructive minimally invasive and surgical techniques have beenused when conservative measures fail [BOSWELL M V, et al. Interventionaltechniques: evidence-based practice guidelines in the management ofchronic spinal pain. Pain Physician 10(1, 2007):7-111; LAVELLE W F,Lavelle E D, Smith H S. Interventional techniques for back pain. ClinGeriatr Med 24(2, 2008):345-68]. Minimally invasive techniques includeIntradiscal electrothermal therapy (IDET), which involves theapplication of heat via a needle that is inserted transcutaneously intothe disc [DERBY R, Eek B, Chen Y, O'neill C, Ryan D. IntradiscalElectrothermal Annuloplasty (IDET): A Novel Approach for TreatingChronic Discogenic Back Pain. Neuromodulation 3(2, 2000):82-88].Alternatively, radiofrequency annuloplasty is a technique used to targetthe affected area using a needle to deliver radiofrequency energy fordestructive purposes [HELM S, Hayek S M, Benyamin R M, Manchikanti L.Systematic review of the effectiveness of thermal annular procedures intreating discogenic low back pain. Pain Physician 12(1, 2009):207-232].Rather than using heat to destroy nerves in the affected area, it hasbeen proposed that they may be destroyed using ionizing radiation [U.S.Pat. No. 7,634,307, entitled Method and apparatus for treatment ofdiscogenic pain, to SWEENEY].

Surgical techniques are also used to remove a large portion of the discfollowed by a fusion procedure between the two adjoining vertebralbodies [CHOU R, Baisden J, Carragee E J, Resnick D K, Shaffer W O,Loeser J D. Surgery for low back pain: a review of the evidence for anAmerican Pain Society Clinical Practice Guideline. Spine 34(10,2009):1094-1109; LAVELLE W, Carl A, Lavelle E D. Invasive and minimallyinvasive surgical techniques for back pain conditions. Med Clin North Am91(2, 2007):287-298; SCHWENDER J D, Foley K T, Holly L T, Transfeldt, EE. Minimally Invasive Posterior Surgical Approaches to the Lumbar Spine.Chapter 21, pp. 333-341 In: The Spine, Fifth Edition (Harry N.Herkowitz, Richard A. Balderston, Steven R. Garfin, Frank J. Eismont,eds). Philadelphia: Saunders/Elsevier, 2006; GRIFFITH S L, Davis R J,Hutton W C. Repair of the Annulus Fibrosus of the Lumbar Disc. Chapter12 (pp 41-48), In: Nucleus Arthroplasty Technology in Spinal Care:Volume II—Biomechanics & Development. Davis R, Cammisa F P, Girardi F P,Hutton W C, Editors. Bloomington, Minn.: Raymedica Co, 2007].

As described in the above-cited publications, all of these techniqueshave varying degrees of success, and pain relief is generally temporary.A problem with IDET and similar minimally invasive techniques is thatdestruction of nociceptors within the posterior annulus is variable andincomplete. In addition, the offending region involving the PLL is notaddressed.

Several patents or patent applications disclose methods similar toradiofrequency annuloplasty, wherein an array of electrodes (a lead) isintroduced into the disc (but not into the epidural space adjacent tothe disc) to thermally ablate disc tissue. In U.S. Pat. No. 8,066,702,entitled Combination electrical stimulating and infusion medical deviceand method, to RITTMAN, III, et al., radiofrequency energy istransmitted to tissue surrounding the lead, thereby ablating the tissue.U.S. Pat. No. 6,772,012 and U.S. Pat. No. 7,270,659, entitled Methodsfor electrosurgical treatment of spinal tissue, to RICART et al., alsodescribe controlled heating to ablate various tissues in or around thevertebral column using a radiofrequency voltage, including possibly aposterior longitudinal ligament. A thermal ablation method that may alsobe directed to the posterior longitudinal ligament, involvingelectrosurgically coagulating nerve tissue within the posterior of theannulus fibrosus by applying heat, is disclosed in U.S. Pat. No.7,331,956, entitled Methods and apparatus for treating back pain, toHOVDA et al. Similarly, abandoned application U.S. Ser. No. 11/105,274,corresponding to publication No. US20050261754, entitled Methods andapparatus for treating back pain, to WOLOSZKO et al., describesdenervation of an intervertebral disc or a region of the posteriorlongitudinal ligament by the controlled application of heat to a targettissue. All of the methods disclosed in those patents affect theoffending region irreversibly, through the application of joule heating.In contrast, in the preferred embodiments of the present invention,stimulation devices, such as electrodes, are introduced to affect theoffending region reversibly, not irreversibly. Alternatively, in otherembodiments of the present invention, the offending region may beaffected irreversibly when the reversible methods fail to reduce thepatient's pain.

Lower back pain has been treated reversibly by stimulation of the spinalcord, using electrical stimulation devices that are used generically tomodulate neuronal function [ten VAARWERK I A, Staal Mi. Spinal cordstimulation in chronic pain syndromes. Spinal Cord 36(10, 1998):671-682;NORTH R B, Wetzel F T. Spinal cord stimulation for chronic pain ofspinal origin: a valuable long-term solution. Spine 27(2,2002):2584-2591; STOJANOVIC M P, Abdi S. Spinal cord stimulation. PainPhysician 5(2, 2002):156-166; BAROLAT G, Sharan A. Spinal CordStimulation for Chronic Pain Management. In Pain Management for theNeurosurgeon: Part 2, Seminars in Neurosurgery 15 (2, 2004):151-175; R.B. NORTH. Neural interface devices: spinal cord stimulation technology.Proceedings of the IEEE 96(7, 2008): 1108-1119; Allen W. BURTON, PhillipC. Phan. Spinal Cord Stimulation for Pain Management. Chapter 7, pp. 7-1to 7-16, In: Neuroengineering (Daniel J. DiLorenzo and Joseph D.Bronzino, eds). Boca Raton: CRC Press, 2008; Steven FALOWSKI, AmandaCelii, and Ashwini Sharan. Spinal cord stimulation: an update.Neurotherapeutics 5(1, 2008):86-99; KUNNUMPURATH S, Srinivasagopalan R,Vadivelu N. Spinal cord stimulation: principles of past, present andfuture practice: a review. J Clin Monit Comput 23(5, 2009):333-339].Other examples of electrical stimulation are deep brain stimulation fortreatment of Parkinson's disease or other movement disorders, complexregional pain syndrome (previously referred to as reflex sympatheticdystrophy), post herpetic neuralgia and others. In addition to centrallymediated nerve stimulation, peripheral nerve stimulation has also beenused to successfully treat neuropathic pain syndromes such as occipital,trigeminal, and post herpetic neuralgias [WHITE P F, Li S, Chiu J W.Electroanalgesia: its role in acute and chronic pain management. AnesthAnalg 92(2, 2001):505-513; STANTON-HICKS M, Salamon J. Stimulation ofthe central and peripheral nervous system for the control of pain. JClin Neurophysiol 14(1, 1997):46-62].

Although spinal cord electrical stimulation is an established method fortreating axial lower back pain, it produces improvement in back pain inonly approximately 50% of patients [John C. OAKLEY. Spinal CordStimulation in Axial Low Back Pain: Solving the Dilemma. Pain Medicine 7(Supplement s1, 2006):558-563]. The devices used for spinal cordstimulation comprise: (1) electrodes that are implanted in the spine,and (2) a power source that delivers electrical pulses to theelectrodes. The present invention also discloses electrodes that areimplanted in the spine and a power source that powers the electricalpulses that are delivered to the electrodes, but which are not a spinalcord stimulator for reasons described below.

Commercially available general-purpose electrodes and pulse generatorsthat are used for spinal cord stimulation and peripheral nervestimulation could in principle also be used to electrically stimulatethe lumbar posterior longitudinal ligament and adjoining outer posteriorannulus fibrosus of the intervertebral discs. However, as disclosedbelow, such general-purpose stimulators are not well-suited for theobjectives of the present invention. Furthermore, devices according tothe present invention are not spinal cord stimulators for treating backpain. In fact, electrodes in the present invention are placed in thecanal defined by the vertebral foramen in the lumbar region and in mostcases, below the spinal cord, where the cauda equina rather than thespinal cord occupies that opening. Heretofore, when the lumbar columnshave been stimulated with spinal cord stimulator devices, it has beenfor purposes of spasticity control or the generation of muscle activityin spinal cord injury patients, not for purposes of treating back pain[DANNER S M, Hofstoetter U S, Ladenbauer J, Rattay F, Minassian K. Canthe human lumbar posterior columns be stimulated by transcutaneousspinal cord stimulation? A modeling study. Artif Organs 35(3,2011):257-262]. In order to explain differences between the presentinvention and spinal cord stimulators, the development and use of spinalcord stimulators will first be summarized.

Spinal cord electrical stimulation for the treatment of pain was firstperformed in 1967 by SHEALY and colleagues [SHEALY C N, Mortimer J T,Reswick J B. Electrical inhibition of pain by stimulation of the dorsalcolumns: preliminary clinical report. Anesth Analg 46(4, 1967):489-491].In the decade that followed, many variations in technique were tried.Electrodes were implanted at different locations relative to the spinalcord: in endodural, subdural, subarachnoid, and epidural positions. Todo so, a significant amount of spinal bone was often removed, in orderto allow placement of the electrodes (a surgical laminectomy, orcomplete removal of vertebral lamina). In other cases, a small window ofbone was drilled over the area, using less invasive techniques(laminotomy, or partial removal of vertebral lamina). Finally, minimallyinvasive techniques were developed to implant a catheter-like electrodelead percutaneously.

Rather than implanting the electrodes one-by-one, leads (also known aselectrode arrays) were developed wherein multiple electrodes weremounted on, in, or about an insulating substrate, and the lead was thenimplanted. Such leads may have the shape of a plate and are said tocontain paddle electrodes, plate electrodes, ribbon electrodes, surgicalelectrodes or laminotomy electrodes. For percutaneous implantation, theleads may also have the shape of a wire or catheter, which are said tocontain percutaneous or wire electrodes.

In almost all cases, the electrodes were implanted on the posterior sideof the spinal cord, i.e., the side most accessible from the back.However, in 1975 LARSON et al. and HOPPERSTEIN implanted electrodes onthe anterior side of the spinal column, in an attempt to improve the lowsuccess rate of spinal cord stimulation in reducing pain [Sanford J.LARSON, Anthony Sances, Joseph F. Cusick, Glenn A. Meyer, ThomasSwiontek. A comparison between anterior and posterior spinal implantsystems. Surg. Neurol. 4(1975):180-186; Reuben HOPPENSTEIN. Electricalstimulation of the ventral and dorsal columns of the spinal cord forrelief of chronic intractable pain: preliminary report. Surg. Neurol.4(1975):187-194]. In contrast to the present invention, though, they didnot implant the anterior electrodes within the anterior epidural space,they did not attempt to implant electrodes in the lumbar spine, and theywere not concerned with the treatment of back pain. Furthermore, theanteriorly-placed electrodes were configured to stimulate the spinalcord, which is different than the configuration that would stimulateonly nerves in the posterior longitudinal ligament and the underlyingannulus fibrosus as in the present invention.

The anterior location of the electrode in the epidural space isparticularly relevant to the present invention. The epidural space isthe space within the spinal canal lying outside the dura mater (dural orthecal sac), which contains lymphatics, spinal nerve roots, loose fattytissue, small arteries, and blood vessels. The epidural space surroundsthe dural sac and is bounded by the posterior longitudinal ligamentanteriorly, the ligamenta flava and the periosteum of the laminaeposteriorly, and the pedicles of the spinal column and theintervertebral neural foramina containing their neural elementslaterally. The space communicates freely with the paravertebral spacethrough the intervertebral neural foramina. For spinal cord stimulation,the electrodes are now invariably implanted in the posterior epiduralspace.

However, a percutaneous lead may be accidentally introduced into theanterior epidural space, which is considered to be an error, and thelead is withdrawn. Thus, FALOWSKI et al. write that “Frequently, theelectrode curves around the dural sac and ends in the ventral epiduralspace. A gentle lateral curve of the electrode shortly after its entryinto the epidural space should arouse the suspicion that it is directingventrally around the dural sac. Absolute confirmation of the ventrallocation arises from the stimulation generating violent motorcontractions or observation [by fluoroscopy] in the lateral plane whichwould readily disclose the anterior position of the electrode tip.”[Steven FALOWSKI, Amanda Celii, and Ashwini Sharan. Spinal cordstimulation: an update. Neurotherapeutics 5(1, 2008):86-99]. Thus, incontrast to the present invention, implantation of a spinal cordelectrode in the anterior epidural space is considered to be an error,and in any event, the implantation of spinal cord stimulator electrodesis not performed in the lumbar spine (e.g., L3-L5). Furthermore, in thepresent invention, the electrical stimulus is directed towards theposterior longitudinal ligament in such a way that motor contractionsare not induced by the stimulation. Applicant is unaware of thedeliberate percutaneous implantation of a spinal cord stimulator in theanterior epidural space. As disclosed herein, such deliberateimplantation in the anterior epidural space would likely involve adifferent anatomical route than the interlaminal approach that is takenfor access to the posterior epidural space. Thus, as is known from themethods for performing epidural injections, to reach the anteriorepidural space, a transforaminal anatomical approach may be taken, andfor lumbar vertebrae, a sacral route may be taken as well [Mark A.HARRAST. Epidural steroid injections for lumbar spinal stenosis. CurrRev Musculoskelet Med 1:(2008):32-38].

Spinal cord stimulation is performed for the treatment of back pain, butit involves stimulation in vertebrae other than the lumbar spine L3-L5.The vertebral location of the stimulator electrodes is selected on thebasis of the location of the patient's pain. BAROLAT et al. mapped thebody areas that may be targeted by stimulation of the spinal cord indifferent vertebrae and made the following observations concerning howbest to stimulate to treat lower back pain. “It is very difficult tostimulate the low back only, without intervening chest/abdominal wallstimulation . . . . (1) the peak curve for low-back stimulationcoincides with the peak curve for the chest/abdominal wall . . . (2) thechest/abdominal wall region has a higher percentage of stimulation thanthe low back; and (3) the chest/abdominal wall area has a lowerstimulation threshold than the low back. All of these factors contributeto the challenge of being able to direct stimulation selectively to thelow back without interference from the body walls. In our experience,the best location was about T9-10, with the electrode placed strictly atthe midline.” [BAROLAT G, Massaro F, He J, Zeme S, Ketcik B. Mapping ofsensory responses to epidural stimulation of the intraspinal neuralstructures in man. J Neurosurg 78(2, 1993):233-239].

It is therefore not surprising that the effectiveness of spinal cordstimulation for lower back pain is equivocal. Most reviews of itseffectiveness have been made in connection with the treatment of FailedBack Surgery Syndrome (FBSS), which may involve pain in locations inaddition to the back (e.g., the leg). A Cochrane review of randomclinical trials for the treatment of FBSS by spinal cord stimulationconcluded that although one clinical trial does provide some limitedevidence in favor of spinal cord stimulation, the numbers are small andas a result the study fails to achieve statistical significance[MAILIS_GAGNON A, Furlan A D, Sandoval J A, Taylor R. Spinal cordstimulation for chronic pain. Cochrane Database Syst Rev.2004(3):CD003783, pp. 1-16, updated 2009]. Other reviews indicate thatup to 40 percent of such FBSS patients do not benefit substantially fromspinal cord stimulation [ELDABE S, Kumar K, Buchser E, Taylor R S. Ananalysis of the components of pain, function, and health-related qualityof life in patients with failed back surgery syndrome treated withspinal cord stimulation or conventional medical management.Neuromodulation 13(3, 2010):201-209; FREY M E, Manchikanti L, Benyamin RM, Schultz D M, Smith H S, Cohen S P. Spinal cord stimulation forpatients with failed back surgery syndrome: a systematic review. PainPhysician 12(2, 2009):379-397].

Similarly, a review found that spinal cord stimulation for treatmentspecifically of discogenic pain might be useful, as evidenced by areduction in opioid usage by such patients, but the review involved onlya small number of patients [VALLEJO R, Manuel Zevallos L, Lowe J,Benyamin R. Is Spinal Cord Stimulation an Effective Treatment Option forDiscogenic Pain? Pain Pract 12(3, 2012):194-201]. OAKLEY reviews theproblem of why approximately 50% of patients with lower back pain arenot helped by spinal cord stimulation. He suggests that advances instimulator technology may help, such as properly selecting the numberand location of stimulator electrodes, using pulse generators withindependent current control over each lead contact electrode, andoptimizing the stimulation waveform (e.g., pulse width) [John C. OAKLEY.Spinal Cord Stimulation in Axial Low Back Pain: Solving the Dilemma.Pain Medicine 7 (Supplement s1, 2006):558-563]. In regards to stimuluswaveform optimization, A L-KAISY et al. suggest that the use of highfrequency pulses may help [Adnan A L-KAISY, Iris Smet, and Jean-PierreVan Buyten. Analgesia of axial low back pain with novel spinalneuromodulation. Poster presentation #202 at the 2011 meeting of TheAmerican Academy of Pain Medicine, held in National Harbor, M D, Mar.24-27, 2011].

The above-cited literature demonstrates that the treatment of lower backpain by invasive electrical stimulation is in need of improvement. Tothat end, the present invention is motivated by the fact that theinnervation of the posterior longitudinal ligament and the underlyingannulus fibrosus may be the predominant origin of the lower back pain.Thus, KUSLICH et al. write that “ . . . we had the opportunity toperform more than 700 operations on the lumbar spine while using localanesthesia . . . . Back pain could be produced by stimulation of severallumbar tissues, but by far, the most common tissue of origin [of backpain] was the outer layer of the annulus fibrosus and posteriorlongitudinal ligament.” [KUSLICH S D, Ulstrom C L, Michael C J. Thetissue origin of low back pain and sciatica: a report of pain responseto tissue stimulation during operations on the lumbar spine using localanesthesia. Orthop Clin North Am 22(2, 1991):181-187].

To affect the innervation of the lumbar posterior longitudinal ligament,the electrodes that stimulate them need to be placed in the lumbarspine, which is not done in spinal cord stimulation for back pain. Atthat lumbar location, the cauda equina is situated posterior to theposterior longitudinal ligament. Placement of an electrode between theposterior longitudinal ligament and the cauda equina would cause thecauda equina to be stimulated, if the electrode were to stimulate in alldirections. Such stimulation of the cauda equina would be veryundesirable because it would cause leg movements resulting fromstimulation of nerve roots within the cauda equina.

In fact, there are only a few reasons for electrically stimulating thecauda equina, and they are not relevant to the treatment of discogenicback pain. Electrical stimulation of the cauda equina, through highvoltage percutaneous or transcutaneous stimulation above the lumbarvertebrae, is sometimes done in order to assess conduction in the caudaequina, which is accompanied by electromyographic activity in muscles ofa lower limb. However, this does not involve placement of an electrodein the epidural space [Maertens de NOORDHOUT A, Rothwell J C, Thompson PD, Day B L, Marsden C D. Percutaneous electrical stimulation oflumbosacral roots in man. J Neurol Neurosurg Psychiatry 51(2,1988):174-81]. Electrodes have been placed in the posterior epiduralspace in the vicinity of the conus medullaris and cauda equina, but thisis done only for purposes of mapping or monitoring, not for thetreatment of lower back pain, and not for purposes of stimulating theposterior longitudinal ligament or posterior annulus fibrosus [KOTHBAUERK F, Deletis V. Intraoperative neurophysiology of the conus medullarisand cauda equina. Childs Nerv Syst 26(2, 2010):247-253]. In anothersituation, a special electrode is used to enable restoration of at leastpartial control over lower-body functions that are directed by nervesemerging from the end of the spinal cord. The electrode is designed forintroduction into the lower end of the dura beneath the conus of thespinal cord, to float in the intrathecal space that is loosely occupiedby the sacral roots and other nerves of the cauda equina. Thus, thatelectrode is not implanted in the epidural space, and it is not intendedto treat lower back pain or stimulate the posterior longitudinalligament or posterior annulus fibrosus [U.S. Pat. No. 4,633,889,entitled Stimulation of cauda-equina spinal nerves, to TALALLA et al].

Therefore, if one wishes to electrically stimulate the lumbar posteriorlongitudinal ligament to treat back pain reversibly, but avoidstimulation of other structures adjoining the anterior epidural space,at least two problems must be addressed. One is that the electricalstimulation must be directed specifically to the posterior longitudinalligament and its underlying structures, and this involves not onlydesigning an asymmetric structure for the lead, but also the design ofdirectionality of its insertion into the patient. A second problem isthat electrodes, particularly percutaneous electrodes (wire, orcatheter-like electrodes) have a tendency to migrate or rotate, suchthat even if the electrode were initially directed to stimulate theposterior longitudinal ligament, it may eventually rotate or migrate,thereby accidentally stimulating other tissues. The present invention isdesigned to address both of these problems. It also addresses theproblem of selectively ablating the nerves if the reversible stimulationdoes not work.

These problems are not addressed in the patents that are related to thepresent invention. In U.S. Pat. No. 7,069,083, U.S. Pat. No. 7,831,306,and U.S. Pat. No. 8,086,317, all entitled System and method forelectrical stimulation of the intervertebral disc, to FINCH et al., apercutaneous (wire, or catheter) lead is placed in a disc or justoutside the outer confines of the disc, circumferentially along theentire perimeter of the annulus of the disc. The lead is not placed inthe anterior epidural space, there is no suggestion of stimulating theposterior longitudinal ligament, the electrodes do not stimulate in aparticular direction, and there is no suggestion of how rotationalmigration of its cylindrical lead might be retarded. In U.S. Pat. No.7,945,331, entitled Combination electrical stimulating and infusionmedical device and method, to VILIMS, it is suggested incidentally thathis disclosed percutaneous (wire, or catheter) lead “is well suited fortreatment of other areas along the spine to include the ventral canalalong the posterior longitudinal ligament, ventral dura, and theposterior aspect of the disc.” However, there is no suggestion as to howthe lead would be inserted or used in those locations. In one embodimentof that invention, “the electrodes are not formed circumferentiallyaround the distal portion, but are formed more linearly along one sideof the stimulation lead.” However, that patent does not suggest how suchan electrode would be inserted to selectively stimulate any particulartissue, and it does not suggest how subsequent rotational migration ofits cylindrical lead could be retarded. Furthermore, that patent isconcerned with managing sacroiliac joint pain in a sacrum of a patient,not discogenic lumbar pain. None of the above-cited patents disclosedevices that would almost completely cover a pain-generating region,such as the entire innervation of an offending lumbar posteriorlongitudinal ligament and adjacent posterior annulus fibrosus of theintervertebral disc(s).

In view of the foregoing, there is a need for a lumbar vertebral columnelectrical stimulator lead that is adapted for directional insertioninto the anterior epidural space adjacent to the posterior longitudinalligament; that will provide adjustable and reversible non-destructivemodulation of nerves in the posterior longitudinal ligament andunderlying annulus fibrosus to effectively reduce back pain, whenconnected to a pulse generator; that will cover the pain-generatingregion; that will stimulate only the posterior longitudinal ligament andunderlying annulus fibrosus, but not nearby tissue such as the caudaequina or nerve roots; and that is not susceptible to accidentalrotation or migration.

For patients in which such reversible electrical stimulation does notreduce the pain significantly, there would also be a need for alternatereversible stimulation modalities and procedures (e.g., nerve cooling)that may succeed in reducing the pain, either alone or in combinationwith reversible electrical stimulation, such that all such stimulationmodalities could be evaluated simultaneously using the same implanteddevice. Whether reversible electrical stimulation or an alternatereversible stimulation modality is used, diagnostic procedures areneeded in order to characterize the pathophysiology of the patient'soffending nerves, so as to guide the selection of parameters that areused to perform the stimulation (waveform type, stimulation amplitude,frequency, etc.). It is also intended that as a last resort, thedisclosed devices may be used to irreversibly damage the offendingnerves, preferably without the use of thermal ablation thatindiscriminately damages material near the offending nerves, such ascollagen in the posterior longitudinal ligament.

SUMMARY OF THE INVENTION

The present invention is directed to methods and devices for thetreatment of chronic lower back pain that may result from a degeneratedor injured intervertebral disc. In a preferred embodiment, an array ofelectrodes, along with a pulse generator that is connected to theelectrodes, are used to deliver electrical impulses to nociceptiveand/or other nerves located within the posterior longitudinal ligament(PLL) of the lumbar spine and the superficial layer of the dorsal aspectof the annulus fibrosus that lies under the PLL. In alternateembodiments of the invention, the energy directed to nerves in the PLLmay be from light, mechanical vibrations or thermal energy, or thenerves may be cooled.

According to the invention, the stimulation in this region may reduceback pain in a patient reversibly, adjustably, and with almost completecoverage of the pain-generating region, for example, by interfering withor modulating afferent pain signals to the brain that originate in thosenerves. All stimulating electrodes, light sources, vibrators, heaters orcoolers are unidirectional, such that the electrodes or otherenergy-producing devices are located on one side of the insulatingmaterial to which they are attached, e.g., a flexible, inert siliconeelastomer (such as Silastic™) or similar flexible material, to preventstimulation to the overlying thecal sac and the nerves containedtherein.

Implantation of the stimulator device may involve a two-step process. Atemporary array of electrodes or other energy-producing devices (a lead)may first be implanted transcutaneously and attached by wires, or byoptical fibers in the case of light sources, to an external(nonimplanted) pulse generator. One or more of such leads are insertedfor the trial under sterile conditions under local anesthesia, with orwithout conscious sedation. The temporary leads have energy-producing orenergy-transmitting devices that are disposed linearly along a side ofthe lead. The temporary leads are straight and thin, as compared to thepermanent leads that may subsequently be implanted, in order tofacilitate transcutaneous implantation of the temporary leads. Althoughtemporary leads may be placed longitudinally or horizontally, horizontalplacement at one or more vertebral levels via a transforaminal approachwill be most common. For implantation of the temporary leads,epidurography is used in order to see that the cauda equina and nerveroots are safely negotiated. Whether the lead is temporary or permanent,its implantation is accompanied by intra-operative electrophysiologicmonitoring (somatosensory-evoked potential measurement, spontaneous ortriggered electromyography, etc.) to assess the functional integrity ofthe cauda equina and nerve roots and to detect if that functionalintegrity is compromised during insertion and/or stimulation of thelead(s).

Because of the potential danger of accidentally stimulating the thecalsac and nerves contained therein, the temporary lead is speciallydesigned to prevent accidental rotation of energy-producing orenergy-transmitting devices of the lead towards the thecal sac. Thesides of the lead preferably comprise fins that protrude from the mainbody of the lead which, when inserted into the tissue of the anteriorepidural space, will prevent rotation and migration of the leads.Furthermore, although the body of the temporary lead may be shaped in aconventional catheter-like cylindrical form, a flat shape with a roundedor curved tip is preferable in order to prevent rotation and to maintaindirectionality of electrodes or other energy-transmitting devices of thelead toward the PLL. In order to implant such flat and/or finned leadsinto a suitable position, special percutaneous implantation methods anddevices are used. Intraoperative electrophysiological monitoring is alsoused to confirm that the thecal sac is not being damaged or stimulatedby a lead, either during the lead's insertion or when pulses of energyare applied to the lead.

If nerve stimulation via the temporary energy-producing devices issuccessful in reducing back pain, a permanent array of energy-producingdevices is implanted and attached by wires to an internal (implanted)pulse generator, or in the case of the transmission of light they may beconnected with optical fibers. The permanent energy-producing devicesare generally disposed nonlinearly across the surface of a paddle lead(plate lead or surgical lead). The direction and route of permanentelectrode insertion may be chosen based on the implanter's preferenceand the extent of the pain generating region. The objective is for theenergy emitted or transmitted by the energy-producing devices to crossthe path of nerves identified as the stimulation target. The permanentpaddle leads are specially designed to contour the posterior vertebralcolumn, such that the surface area of the contact electrodes narrows inthose regions bound by two pedicles. This configuration also aids inanchoring the leads in place. Similar to temporary leads, permanentleads may be placed horizontally along the width of the posteriorannulus of an intervertebral disc and overlying PLL or placedlongitudinally along the PLL that spans the distance between one or moreintervertebral discs. The length and width of the paddle leads will varyto accommodate the corresponding dimensions of the pain-generatingregion as measured on CT or MRI in individual patients.

For patients with whom reversible electrical stimulation does not reducethe pain significantly, the invention contemplates that alternatereversible stimulation modalities may succeed in reducing the pain,either alone or in combination with reversible electrical stimulation.Thus, if the implanted device delivers energy to the nerves within theposterior longitudinal ligament and underlying annulus fibrosus viamechanical vibration or light, or if the temperature of the nerves isreversibly modulated or controlled (heated or cooled) using miniaturethermoelectric heat pumps that are integral to the lead device, thenthese alternate stimulation modalities may succeed by virtue of theireffects on the nerves through mechanisms other than electrical effects.

The electrodes of the device may also be used as diagnostic aids, tomonitor spontaneous activity of the nerves that lie under the electrodesand to correlate that spontaneous activity with independent measurementof spinal movement, of fluctuations in autonomic tone and of pain; tocharacterize the electrical conductivity of tissue containing the nervesusing real-time electrical impedance tomography (EIT); and to perform adiagnostic electrical stimulation in order to evoke potentials such as aP300 event-related potential that is related to the patient's perceptionof pain. Furthermore, even if the alternate energy modalities are notused to treat the patient, they may also be used as diagnostic aids tocharacterize the pathophysiology of the offending nerves. For example,laser light emitted by the device may be used for laser Dopplerflowmetry, to measure blood flow in the posterior longitudinal ligamentand underlying annulus fibrosus, thereby serving as a measure of thelocal sympathetic tone.

The diagnostic data may then be used to guide selection of parametersfor the nerve stimulation using the different energy modalities, evenincorporating automatic analysis of the data into a closed-loop systemthat performs the stimulation autonomously. In particular, the laserDoppler flowmetry may be used to assess the extent to which stimulationof the nerves in the PLL and/or underlying annulus fibrosus, using aparticular set of stimulation parameters (amplitude, frequency, pulsewidth, etc.) or more generally using a particular type of waveform, iseither enhancing or inhibiting the activity of the sympathetic nerves,which in turn modulate the activity of nearby nociceptors. Anyaccompanying decrease in the measured level of pain in the patient cantherefore be taken as evidence that the electrical impulses to thesympathetic nerves at least partially relieve the pain, for thosestimulation parameters or waveforms. As another example, measuredeffects of the electrical stimulation on the patient's pain, as afunction of the modulated temperature of those nerves, may be used tojointly select the electrical stimulation parameters and appliedtemperature.

As a last resort, the disclosed devices may be used to irreversiblydamage the offending nerves, preferably without the use of thermalablation that indiscriminately damages material near the offendingnerves, such as collagen in the posterior longitudinal ligament. Inparticular, electrodes of the stimulator may be used to performnon-thermal irreversible electroporation, light energy may be used todamage nerves by photooxidation with or without the use of aphotosensitizer, trauma induced by high-amplitude mechanical vibrationmay be used to deliberately damage selected nerves, and irreversibledamage to the nerves may occur following their maintenance at low butnon-freezing temperatures. Although thermal ablation may also be used todamage the nerves by joule heating and/or by dielectric heating ofproteins, a thermal insulator covers substantially all of the caudaequina or thecal sac, thereby shielding the cauda equina, thecal sac andnerve roots from the heat that could cause damage. For other stimulationmodalities, the cauda equina and other sensitive tissue is protectedfrom iatrogenesis using shock absorbing material in the case ofmechanical vibration, light shielding in the case of undesiredphotooxidation, and the conduction/dissipation of unwanted heat in thecase of cooling with a thermoelectric heat pump.

Considered as a system, the invention comprises the followingcomponents:

1) Specially designed temporary leads (percutaneous type with linearlyarranged electrodes and/or stimulation devices involving the delivery ofother forms of energy) and permanent leads (paddle leads with generallynonlinearly arranged electrodes and/or other stimulation devices), withthe electrodes and/or other stimulation devices situated in a flexible,inert silicone elastomer (such as Silastic™) or similar flexibleinsulating material, wherein pulses of energy are transmitted from theelectrodes and/or other stimulation devices to adjacent tissueunidirectionally.2) Pulse generators designed for internal (implanted) and for externaluse that transmit electrical pulses to the electrodes via wires and/orthat transmit pulses to stimulation devices involving other forms ofenergy, and a programmer that controls the pulse generator. Theprogrammer is used to adjust each electrode's electrical pulse rate,duration, amplitude and anode/cathode configuration, as well as eachelectrode's state of connection or disconnection to the pulse generator.The programmer may also be used to adjust pulses for other stimulationdevices that are mounted in the lead. The programmer may provide controlsignals to the pulse generator using radiofrequency or infraredtransmission, and it may also provide power inductively to the pulsegenerator if the pulse generator is not powered by batteries. The pulsegenerator may also communicate wirelessly with a separate computer thatmay serve as a programmer and that may also integrate data that are alsoreceived from other non-invasive devices such as scalp electrodes orelectrodermal sensors. Diagnostic data from the lead may also betransmitted to the computer, e.g., via the pulse generator, particularlydata from an accelerometer, a stress sensor, a thermometer, and theelectrodes themselves.3) Specially designed surgical aides for implantation of the leads, suchas a trocar, obturator, stylet, lead blank, introducer cannula,anchoring tabs, and tools used for connecting the lead to the pulsegenerator.

However, it should be understood that application of the methods anddevices is not limited to the examples that are given. The novelsystems, devices and methods for diagnosing and treating conditionsusing the disclosed stimulation devices are more completely described inthe following detailed description of the invention, with reference tothe drawings provided herewith, and in claims appended hereto. Otheraspects, features, advantages, etc. will become apparent to one skilledin the art when the description of the invention herein is taken inconjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 shows the spine in a cross section perpendicular to its longaxis, cut through one of the lumbar discs.

FIG. 2 shows a cross section of the lumbar spine viewed from the side(left-to-right).

FIG. 3 shows a posterior-to-anterior view of the lumbar spine, viewedobliquely on the left side of the patient.

FIG. 4 shows a posterior-to-anterior view of the innervation of theposterior longitudinal ligament (PLL) and of the annulus fibrosus of theintervertebral disc that lies adjacent to the PLL.

FIG. 5 shows a percutaneous flat lead and a pulse generator that may beused to stimulate nerves in the posterior longitudinal ligament andunderlying annulus fibrosus, according to the present invention. In FIG.5A, the lead is shown to be a percutaneous flat lead, and in FIG. 5B, adirectional indicator is shown to point in the correct direction whenthe lead has been inserted correctly.

FIG. 6 shows methods and devices for inserting the percutaneous lead ofFIG. 5 into the anterior epidural space of a patient. Entry into thatspace for the L4-L5 disc is shown in FIGS. 6A and 6B, in a side view andin a posterior view, respectively.

FIG. 7 shows exemplary paddle leads that may be used to stimulate nervesin the posterior longitudinal ligament and underlying annulus fibrosus,according to the present invention. The lead shown in FIG. 7A isintended to be placed horizontally within the anterior epidural space,and the lead shown in FIG. 7B is intended to be placed vertically(longitudinally) within the anterior epidural space.

FIG. 8 shows exemplary paddle leads like the ones shown in FIG. 7,except that the leads are shown to also comprise devices that effectstimulation through the application of light, mechanical vibrations, andcooling. Pulse generators for those devices are also illustrated. Theleads are also shown to comprise sensors for measuring the physicalstate of the stimulated tissue. The lead shown in FIG. 8A is intended tobe placed horizontally within the anterior epidural space, and the leadshown in FIG. 8B is intended to be placed vertically (longitudinally)within the anterior epidural space.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 5 shows an array of electrodes and a pulse generator that may beused to stimulate nerves in the posterior longitudinal ligament andunderlying annulus fibrosus, according to the present invention. Anarray of electrodes is also known as a lead. In FIG. 5A, the lead 60 isshown to be a percutaneous flat lead. The width of the lead may be, forexample, 0.5 cm. As shown, it contains eight contact electrodes 61,which are embedded in insulating material 62. For example, the contactelectrodes may be made of an alloy of platinum/iridium, and theinsulation material may be made of a flexible, inert silicone elastomer(such as Silastic™), polyurethane or silicone/polyurethane. When thelead is rotated by 90 degrees and sectioned along its axis, wires 63 areseen to connect each contact to corresponding connection points in thePulse Generator 64. The wires 63 may also be embedded in the insulatingmaterial 62. For example, the wires may be made of the conductingmaterial 35NLT-DFT-28% Ag or MP35N-DFT-28% Ag. The pulse generator 64may be powered by batteries, or it may be powered by a radio-frequencydriven passive receiver. If the pulse generator is implanted in apatient, it may be programmed through an external transmitter.

When the lead 60 is rotated by 180 degrees to show its back side, thecontact electrodes 61 are no longer visible. Instead, the locationsabove the contact electrodes (shown with dotted lines) are covered byinsulating material. Consequently, stimulation with the lead 60 occurspreferentially on one of its sides, namely, the side with exposedcontact electrodes 61.

For the invention to function properly, the exposed electrodes 61 shouldface the posterior longitudinal ligament. This is because it is intendedto stimulate nerves in the posterior longitudinal ligament andunderlying annulus fibrosus but avoid stimulating other tissue such asthe thecal sac. To assist in confirmation that the lead is orientedproperly when inserted into the patient, the lead contains one or moreradio-opaque directional indicator 65 that may be visualized usingfluoroscopy. As shown in FIG. 5B, the directional indicator 65 willpoint in the correct direction when the lead has been insertedcorrectly. The insertion of the lead may be horizontal along theintervertebral portion of the PLL 66, or it may placed vertically(longitudinally) along the vertebral portions of the PLL 67, or both. Infact, in addition to the horizontal lead at the L4/L5 disc location,another horizontal lead may be inserted at the L3/L4 disc location orother locations. The vertical lead 67 is shown in FIG. 5B to containsixteen contact electrodes, which will connect to sixteen correspondingconnection points in the pulse generator, but otherwise the longersixteen-contact lead functions like the shorter eight-contact lead.Other items labeled in FIG. 5B are intervertebral fibers of theposterior longitudinal ligament 48, vertebral fibers of the posteriorlongitudinal ligament 49, and pedicles (cut) 40.

The percutaneous lead could be cylindrical or, preferably, flat. Forpurposes of defining flatness, consider a cross section of the leadperpendicular to the long axis of the lead. If that cross section can berepresented by about four or fewer connected straight lines and at mostone curved line, then the lead is flat along the surface containing thelongest straight line. For example, the lead may be rectangular in crosssection perpendicular to its long axis, with one side of the rectanglebeing potentially much longer than its adjacent sides (as in a strap).In either case, it is preferred that the lead will have attached fins 67(which may also be called wings) that inhibit movement or rotation ofthe lead from its preferred orientation. For example, FIG. 5B shows sucha preferred lead orientation. For present purposes, a fin is defined tobe something that resembles a fin in appearance, function, or positionrelative to the main body of the electrical lead. The preferredembodiment of the lead having fins is most useful when used with methodsthat are disclosed below in connection with FIG. 6 for inserting andorienting the lead in the patient. The fins 67 are shown in FIG. 5A inthe positions that they naturally attain when they are free to move.However, it is understood that the fins 67 are also sufficientlyflexible that they may be temporarily bent, approximately flat againstthe main body of the lead, when the lead with attached fins is insertedinto the slightly larger diameter lumen of a needle, cannula, orcatheter. Fins have previously been attached to stimulator leads, butnot as in the present invention. In U.S. Pat. No. 6,654,644, entitledPacemaker electrode, to SANCHEZ-ZAMBRANO, a fin is given a serrated edgeto facilitate its removal from cardiac tissue. In U.S. Pat. No.7,894,913, entitled Systems and methods of neuromodulation stimulationfor the restoration of sexual function, to BOGGS et al, a fin comprisingnon-conductive material is shown to focus (reflect) electricalstimulation energy toward a targeted tissue region and away from anon-targeted tissue region. However, in the present invention, thefocusing of electrical stimulation is due to the arrangement ofelectrodes along one side of the lead, not to the presence of the fins.Furthermore, the fins along the side of the lead of the presentinvention could in principle be made of conducting material, forexample, material containing heavy metals that are radio-opaque, whichwould facilitate imaging of the fins with fluoroscopy. Thecharacteristics of the fins most relevant to the present invention arethat the fins should be flexible enough to be temporarily bent duringpassage through a needle or cannula, but strong enough in the unbentstate to withstand rotation when inserted into the anterior epiduralspace of the patient.

Anatomical considerations related to insertion of a percutaneous lead ofthe present invention are as follows. A venous plexus surrounded byvarious amounts of fat almost entirely fills the anterior epiduralspace. In the thoracolumbar region (T10-L2) the basivertebral veinoriginates from this venous plexus and extends into the vertebralbodies. As the size of the dural sac relative to the epidural spacedecreases at the L4-L5 level, the anterior dura falls away from theposterior longitudinal ligament, and fat fills the anterior epiduralspace. Therefore, the insertion of a lead into the midline of theanterior epidural space will likely encounter decreasing mechanicalresistance as one proceeds from L2 to L5. Consequently, if apercutaneous lead is inserted in the vertical (longitudinal) direction,the preferred direction may be from L5 to L3, as shown in FIG. 5B.Depending on the need to change the direction of the distal end of thelead during its insertion, the lead may also be inserted through aneedle or cannula having a tip that produces deflected movement of awire or some other linear element that is inserted through the needle.

Percutaneous entry into the anterior epidural space is accomplished by atransforminal route, or possibly a caudal approach via the sacral hiatusin the case of leads inserted longitudinally. Another possiblepercutaneous entry route, albeit less likely, is the posteriorlateralinterlaminal approach, especially at the level of L5 and S1 forlongitudinal lead placement. Percutaneous entry to the anterior epiduralspace is performed under fluoroscopic guidance, for example in thetransforaminal approach, wherein a needle is positioned within a safezone of the intervertebral neural foramen, most commonly within a regionjust lateral and cephalad to the margin of the inferior pedicle, dorsalto the vertebral body and caudal to the nerve root (Kambin's triangle),taking care to avoid damage to the nerve root. Endoscopic guidance mayalso be used in this and subsequent implantation steps.

The entry is shown in FIGS. 6A and 6B. Labels in those figurescorrespond to: Touhy epidural needle 70, anterior epidural space 25, L3nerve root 35, L4 nerve root 36, L5 nerve root 37, thecal sac 5, andL4-L5 left neural foramen 71. Fluoroscopic contrast agents willordinarily be injected to traverse the epidural space and outline thedorsal root ganglion, nerve root, and thecal sac, thereby making itpossible to visualize a safe insertion of the needle into the anteriorepidural space [JOHNSON B A, Schellhas K P, Pollei S R. Epidurographyand therapeutic epidural injections: technical considerations andexperience with 5334 cases. AJNR Am J Neuroradiol 20(4, 1999):697-705].A posterolateral approach is an alternative to the conventionaltransforaminal approach, in cases where needle tip positioning in theanterior epidural space is difficult [I. S. LEE, S. H. Kim, J. W. Lee,S. H. Hong, J.-Y. Choi, H. S. Kang, J. W. Song, and A. K. Kwon.Comparison of the temporary diagnostic relief of transforaminal epiduralsteroid injection approaches: conventional versus posterolateraltechnique. American Journal of Neuroradiology 28(2007): 204-208].

More specifically, a scalpel is used to make a small incision where theepidural needle will enter the skin. Under fluoroscopy, a Touhy (orsimilar) epidural needle is inserted as shown in FIG. 6. Entry into theepidural space is confirmed by the ability to blow air into it due tonegative pressure within the epidural space. Fluoroscopic contrastagents may be used at this point to assess the location of the tip ofthe needle relative to the pertinent anatomy such as the nerve root,pedicles, and edge of the thecal sac. A guide wire is then inserted intothe lumen of the needle and positioned at the border of the anteriorthecal sac and underlying PLL. The needle is then withdrawn, leaving theguide wire in place. A rigid introducer cannula is placed over the guidewire and docked on bone just lateral to the anterior edge of the thecalsac where it meets the posterior spinal column. A flexible introducercannula may also be used instead. Alternatively, an obturator may beplaced in the central opening of the introducer cannula and around theguide wire during initial advancement of the introducer cannula toprevent potential blockage of its lumen by tissues. Once the obturatoris removed, fluoroscopic contrast dye can again be used, administeredthrough the cannula, to confirm proper placement of the tip of thecannula. The shape of the cannula and the shape of its lumen is designedto accommodate the shape of the lead: round to accommodate a roundedcatheter-like lead and rectangular to accommodate a flat lead which ispreferable. The orientation of the tip or bevel of the introducercannula is known by corresponding markings on the handle of the cannula.Consequently, the orientation of the tip of the cannula and handle isknown with respect to the orientation of the lead, once the lead isdelivered through the cannula in the desired orientation (i.e., with theelectrodes directed downward towards the posterior vertebral column).Once the cannula is confirmed to be in the proper position, the lead canbe delivered through the cannula and advanced under fluoroscopy into theanterior epidural space and across the posterior vertebral column,again, making sure that the electrode contacts are directed towards thePLL and away from, or opposite, the thecal sac.

If problems arise in advancing the lead into the anterior epiduralspace, the route of the lead to its desired final position in theepidural space may be opened (tunneled). In one embodiment of theinvention, a flexible lead blank used as a trocar may be passed throughthe cannula into the anterior epidural space to create a passageway forthe placement of the lead. The lead blank is preferably made of aflexible alloy such as Type 304 stainless steel with barium sulfate tomake it radio-opaque. The tip of the lead blank is rounded like the truelead to prevent puncturing of the thecal sac during the tunnelingprocess. Once the lead blank has successfully tunneled across theposterior vertebral column in the anterior epidural space, it can beremoved and the lead can then be passed into place through theintroducer cannula as described above. An alternative method ofdelivering a temporary lead, especially one with a greater width than0.5 cm, may include the use of multiple cannulas, each with a largerlumen size than the others, introduced in succession (i.e., one over theother), until the desired lumen size will accommodate the desiredelectrode lead width. The outside and lumens of such cannulas may havecross-sectional shapes that are not circular (e.g., rectangular). Thisalternative method may or may not involve the use of a Touhy (orsimilar) epidural needle and/or guide wire.

Intra-operative electrophysiologic monitoring is performed in order toassure that the lead has not been inserted in the wrong direction and isnot defective [Thomas N. PAJEWSKI, Vincent Arlet and Lawrence H.Phillips. Current approach on spinal cord monitoring: the point of viewof the neurologist, the anesthesiologist and the spine surgeon Eur SpineJ 16(Suppl 2, 2007): 115-129; MALHOTRA, Neil R and Shaffrey, ChristopherI. Intraoperative electrophysiological monitoring in spine surgery.Spine 35(25, 2010):2167-2179]. Preliminary electrical stimulation isthen performed to test operation of the stimulator, confirming thatthere are no motor responses on the part of the patient at lowstimulation voltages. With the lead in place, the introducer cannula isthen fully removed. The lead is subsequently secured in place, e.g., byattaching to the patient's skin or possibly to an interspinous ligament.Alternatively, an anchor is used to secure the lead (e.g., U.S. Pat. No.7,899,553, entitled Lead anchor for implantable stimulation devices, toBARKER). With the lead attached to the pulse generator, the pulsegenerator is now ready to be programmed to obtain a reduction in backpain, as described below.

If a percutaneous lead like the ones shown in FIG. 5 is successful inreducing the patient's back pain after a trial period of typically oneor two weeks, replacement of that lead with one capable of simulating alarger surface area would be warranted [NORTH R B, Kidd D H, Olin J C,Sieracki J M. Spinal cord stimulation electrode design: prospective,randomized, controlled trial comparing percutaneous and laminectomyelectrodes-part I: technical outcomes. Neurosurgery 51(2,2002):381-389]. Such a larger area can be covered by electrodes mountedin a paddle lead (also known as a plate or surgical lead). Two exemplarypaddle leads are shown in FIG. 7. The lead shown in FIG. 7A is intendedto be placed horizontally within the anterior epidural space, across oneof the patient's discs and across nerves within intervertebral fibers ofthe posterior longitudinal ligament. The lead shown in FIG. 7B isintended to be placed vertically (longitudinally) to stimulate nerves invertebral fibers of the posterior longitudinal ligament, as well asportions of two (or more) of the patient's discs and intervertebralfibers of the PLL.

Apart from the fact that electrodes in the percutaneous lead shown inFIG. 5 are arranged linearly, which is in contrast to the electrodes inthe paddle leads shown in FIG. 7 that are disposed non-linearly acrossthe surface of the lead, the construction of the percutaneous and paddleleads are similar. In particular, all stimulating electrodes 61 of thepaddle leads are unidirectional, such that the electrode contacts arelocated on one side of the insulating substrate of the paddle 62 that ismade of a flexible, inert silicone elastomer (such as Silastic™) orsimilar material, to prevent stimulation to the overlying thecal sac andthe nerves therein. It is advantageous to use a somewhat elasticinsulating substrate, in order to accommodate changes in the geometry ofthe discs that accompany flexion and extension [PEARCY M J, Tibrewal SB. Lumbar intervertebral disc and ligament deformations measured invivo. Clin Orthop Relat Res (191, 1984):281-286].

Thus, the electrode contacts in FIG. 7A are visible in the view 95. Whenthat view is rotated by 90 degrees, as in the view labeled as 96, across section of that rotated view would reveal the electrodes 61, wires63 that connect the electrode to a pulse generator (64 in FIG. 5), andchannels 97 through which those wires run. When the view 95 is rotatedby 180 degrees to produce the view labeled as 98, the electrodes are nolonger visible. Thus, only the insulating material may be seen from thatback side (underlying electrode locations are indicated with dottedlines). The view labeled as 98 also shows how the lead is placedhorizontally across one of the patient's discs and across nerves in theintervertebral fibers of the posterior longitudinal ligament and annulusfibrosus, within the anterior epidural space. Radio-opaque directionalindicators 65 are also shown to be located within the leads, allowingthe orientation of the lead to be visualized by fluoroscopy. Suchdirectional indicators may be redundant if the arrangement of electrodesacross the lead is not symmetrical, in which case, the electrodesthemselves may also serve as directional markers.

As shown in FIG. 7B, a longitudinal (or vertical or vertebral) lead willwiden at the disc spaces to accommodate the posterior lateral margins ofthe annulus fibrosus. Such permanent paddle electrodes are speciallydesigned to contour the posterior vertebral column so that the surfacearea of the contact electrodes narrows in those regions bound by twopedicles. This anatomical consideration applies to the horizontal leadshown in FIG. 7A, as well as to the longitudinal lead shown in FIG. 7B.This configuration also aids in anchoring the leads in place. The leadshown in FIG. 7B is shown to contain 32 electrode contacts because itcovers a larger surface area than the lead shown in FIG. 7A (with 16electrode contacts). The length and width of the paddle leads will varyto accommodate the corresponding dimensions of the lumbar discs asmeasured using C T or MRI imaging. The width of the electrode paddleswill be limited to some extent by the distance between two adjacentnerve roots, as estimated from the location of pedicles 40. Thus, thepaddle electrodes shown in FIG. 7 differ from presently available spinalcord paddle leads in that the leads of the present invention should becustom fit for each patient (at least within a narrow range ofdimensions), otherwise the leads will not fit into the patient properly.The distance between two adjacent ipsilateral nerve roots shouldapproximate the ipsilateral interpedicular distance 100 (1.5-2.5 cm),which is slightly less than the contralateral interpedicular distance(2.0-3.0 cm) that varies according to the particular vertebra: 2.0-2.2cm for L3 101, 2.2-2.6 cm for L4 102, and 2.6-3.0 cm for L5 103). Thespace limitation created by the distance between two adjacent nerveroots may warrant two leads to be placed side by side in rare casesrequiring wider coverage. The longitudinal (or vertical) lead length 104will vary depending on the extent and number of discs to be included inthe stimulated area (typically 6.0 to 8.0 cm to achieve a distance thatspans from L3-L4 to L4-L5 and 8.0 to 9.0 cm if extension from L3-L4 toL5-S1 is required). For comparison, the maximum length of the horizontallead shown in FIG. 7A will be approximately the distance measured fromone side of an intervertebral disc to the other 105 (4.0-5.0 cm), and inthe perpendicular direction, the width of the horizontal lead will beapproximately the thickness or height of an intervertebral disc 106(approximately 1.0 cm).

The permanent leads contain small tabs 99 that are used to anchor thelead to bone or other relatively immobile tissue such as the annulusfibrosus, e.g., wherein sutures are passed through the tabs. Theelectrical connection going from the lead to the pulse generator can besituated at the end of the electrode paddle 108 or on the side of thepaddle 109 to accommodate the most suitable region of access forelectrode placement.

Direct access to the region via a standard laminotomy or laminectomyapproach may be used to insert the paddle lead. Thus, a small window ofbone (laminotomy) is drilled over the area using minimally invasivetechniques to allow insertion of the electrodes into the epidural space.Other times, more bone must be removed (laminectomy) to allow safe andaccurate placement of the electrodes. Such an approach may beaccomplished using a minimally invasive or open technique. Thelaminotomy may be performed, for example, by removing lamina (41 in FIG.3) of vertebrae L4 and L5, or alternatively between L5 and 51. As anexample, the initial steps of Technique 39-20 and its FIG. 39-37 inWILLIAMS and PARK describe a method for gaining access to the anteriorepidural space, into which the lead is inserted [Keith D. WILLIAMS andAshley L. Park. Lower Back Pain and Disorders of Intervertebral Discs.Chapter 39, pp. 2159-2236. In: Campbell's Operative Orthopaedics, 11thedition (S. Terry Canale and James H. Beatty, eds). Philadelphia: MosbyElsevier, 2007]. A full laminectomy involving one or more levels mayalso be required in cases in which significant central canal stenosisdoes not allow adequate space within the anterior epidural compartmentto accommodate lead placement. Once placed in the desired location, thelead is then anchored or sutured to firm and relatively immobile tissueor bone to prevent migration or displacement. Because the paddle leadhas an extensive flat surface, rotation of the lead is not an issue, andplacement of the lead with its electrodes facing the posteriorlongitudinal ligament (and its insulating back towards the thecal sac)will prevent stimulation of the thecal sac. However, if there is somenon-rotational migration of the lead, a snare method may be used toreposition the lead [MACDONALD J D, Fisher K J. Technique for steeringspinal cord stimulator electrode. Neurosurgery 69(1 Suppl Operative,2011):ons83-86]. The paddle lead may be inserted using an adaptation ofthe devices described above in connection with the temporary lead, ortools otherwise used for disc surgery may be used, adapted for operationin the anterior epidural space rather than the disc itself [U.S. Pat.No. 6,830,570, entitled Devices and techniques for a posterior lateraldisc space approach, to FREY et al]. Once the paddle lead is secured inplace, wires from the lead are attached to the pulse generator, and thepulse generator is ready to be programmed to obtain a reduction in backpain, as now described.

The stimulator leads are connected with wires to a pulse generator(implanted or external) that is similar to the ones used for spinal cordstimulation. Examples of such pulse generators are found in patents U.S.Pat. No. 7,979,126, entitled Orientation-independent implantable pulsegenerator, to PAYNE et al; U.S. Pat. No. 7,949,393, entitled Implantablepulse generator comprising fractional voltage converter, to VARRICHIO etal; and U.S. Pat. No. 7,930,030, entitled Implantable pulse generatorhaving current steering means, to WOODS et al. Parameters of the pulsesthat are generated by the pulse generator are selected using aprogrammer. Examples of programmers are found in patents U.S. Pat. No.6,622,048, entitled Implantable device programmer, to MANN et al; U.S.Pat. No. 6,249,703, entitled Handheld patient programmer for implantablehuman tissue stimulator, to STANTON et al; U.S. Pat. No. 7,359,751,entitled Clinician programmer for use with trial stimulator, to ERICKSONet al; and U.S. Pat. No. 7,738,963, entitled System and method forprogramming an implantable pulse generator, to HICKMAN et al. Power tothe pulse generator is ordinarily from a fully implantable battery, oralternatively from a radiofrequency system, wherein the power istransmitted through the skin by closely applied transmitting coils [U.S.Pat. No. 3,727,616, entitled Electronic system for the stimulation ofbiological systems, to LENZKES]. As described by LENZKES, the pulsegenerator may also be programmed via radiofrequency signaling thatcontrols the activation, intensity, distribution, and frequency ofelectrode stimulation.

The exemplary pulse generator 64 in FIG. 5A shows that each of theelectrodes of a lead may be programmed to be either disconnected orconnected to the pulse generator. If the electrode is connected, thepulse generator may in principle vary the voltage of each electrodeindependently, considering the external case of the pulse generator tobe a point of voltage reference. In principle, many types of waveformsmay be impressed by the pulse generator upon an electrode [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. Unlike spinal cord stimulation, thestimulation of the present invention may be performed first withsuccessive small subsets of the electrodes of the lead (e.g., 1electrode, or 2 or 3 adjacent electrodes), in order to locate theunderlying nerves that are causing the back pain. Such a mapping willaid in the subsequent programming of the pulse generator, and it mayalso be useful for identifying where to ablate nerves in the event thatreversible stimulation is not successful. This is not to say that thecumulative pain experienced by the patient is necessarily the simplesummation of the pain emanating from individual nerves, because the painsignals from individual nerves may interact with one another to producegreater or lesser pain signals than those from nerves individually.Therefore, the stimulation of small subsets of electrodes of the leadmay be followed by simultaneous stimulation of pairs of such subsets, inorder to also map the interactions between the underlying nerves.

If the pulse generator is like the ones conventionally used for spinalcord stimulation, it will provide rectangular, biphasic, charge-balancedpulses of adjustable rate and duration to each electrode. For theconventional pulse generator, all electrode contacts connected as anodeswill have the same voltage, and all electrode contacts connected ascathodes will have the same voltage. Unipolar stimulation can be appliedonly if the case of the pulse generator is used as a distant anode.Thus, each electrode is conventionally programmed to have one of threestates: disconnected, anode, or cathode [DE VOS C C, Hilgerink M P,Buschman H P, Holsheimer J. Electrode contact configuration and energyconsumption in spinal cord stimulation. Neurosurgery 65(6 Suppl,2009):210-6]. The states V1, . . . , V8 in the pulse generator 64 inFIG. 5A (and FIG. 8B) represent those states.

As noted above, programming of the pulse generator may be aided bypreliminary stimulation involving successive small subsets of theelectrodes of the lead, in order to locate the underlying nerves thatare causing the back pain. More generally, for a lead containing 16 or32 electrodes, the number of possible programmed states is very large,in which case, the selection of the programmed state is preferably donewith the aid of computer simulation [HOLSHEIMER J. Computer modelling ofspinal cord stimulation and its contribution to therapeutic efficacy.Spinal Cord 36(8, 1998):531-540]. For the present invention, themodeling incorporates knowledge of the electrical properties of the discand its surrounding tissue [GU W Y, Justiz M A, Yao H. Electricalconductivity of lumbar annulus fibrosus: effects of porosity and fixedcharge density. Spine 27(21, 2002):2390-2395]. See also the disclosurebelow regarding Laplace's Equation and electrical impedance tomography(EIT). Pulse width is usually set to between 100 to 400 microseconds,but for such modeling, the pulse width is also a variable, which affectsthe area of coverage [LEE D, Hershey B, Bradley K, Yearwood T. Predictedeffects of pulse width programming in spinal cord stimulation: amathematical modeling study. Med Biol Eng Comput 49(7, 2011):765-774].The result of the simulation is a set of programming options, selectedto preferentially stimulate nerves in a preselected target volume. Afteran initial electrode configuration is selected, the configuration may bereprogrammed to optimize its effectiveness, even after the lead isimplanted in the patient [MANOLA L, Holsheimer J, Veltink P H, BradleyK, Peterson D. Theoretical investigation into longitudinal cathodalfield steering in spinal cord stimulation. Neuromodulation (2,2007):120-132].

The amplitude of the pulses is typically chosen to be between 0 and 10 Vand is set to the smallest value that significantly reduces back pain.Generally, pain relief will be experienced between 2 and 4 V, but thisdepends on the electrodes that are used. The frequency of the pulse waveis between about 0.01 and 10,000 Hz, typically between 20 and 120 Hz,and is also set to the value that most significantly reduces back pain.It is understood that “Hz” refers not only to sinusoidal cycles persecond but also to pulses per second in general.

The stimulation parameters must be adjusted empirically for eachpatient, so as to reduce the pain. Evidence for a reduction in pain maycome from the testimony of the patient, from a decrease in the need forpain medication, from a physical examination that determines painlessranges of movement on the part of the patient, and from many othermethods of pain measurement that are described below. Success inreducing pain may be determined within minutes or hours after thestimulation, or it may be gradual over the course of several days orweeks. Thus, there may be an acute reduction in pain, followed by areduction of pain over the course of days or weeks that is due toadaptation of the nervous system. In preferred embodiments of theinvention, the patient is allowed to turn the stimulation on or off asthe need arises, and may also adjust parameters of the stimulation tooptimize the therapy. The pain might be replaced with paresthesia thatmay be ignored by the patient. The reason that the stimulationparameters must be adjusted for each patient is related to the fact thatthe mechanisms responsible for the sensation of pain are complex, andthey may vary from patient to patient, as now described.

The afferent nerve fibers in the lumbar posterior longitudinal ligament,the dorsal aspect of the annulus fibrosus, and the connective tissuebetween the posterior longitudinal ligament and annulus fibrosus areprincipally mechanosensitive nociceptive fibers, classified into GroupIII and Group IV types, with a high mechanical threshold for activation.Most are unmyelinated, and many have free nerve endings. In somestudies, it is found that a superficial layer of the nerves isassociated with autonomic nerves, and a deeper layer may have a purelynociceptive function. Morbid mechanical stress associated with discabnormality and chemical stress induced by inflammation may sensitizeand stimulate these nociceptive fibers in ways that are not likely undernormal conditions. Such abnormal conditions may also cause growth of thenerve fibers in the direction of disc inflammation, mediated by nervegrowth factor [SEKINE M, Yamashita T, Takebayashi T, Sakamoto N, MinakiY, Ishii S. Mechanosensitive afferent units in the lumbar posteriorlongitudinal ligament. Spine26(14, 2001): 1516-1521; PENG B, Wu W, HouS, Li P, Zhang C, Yang Y. The pathogenesis of discogenic low back pain.J Bone Joint Surg Br 87(1, 2005): 62-67; COPPES M H, Marani E, Thomeer RT, Groen G J. Innervation of “painful” lumbar discs. Spine 22(20,1997):2342-2349; Y. AOKI, K. Takahashi, S. Ohtori & H. Moriya:Neuropathology Of Discogenic Low Back Pain: A Review. The InternetJournal of Spine Surgery 2 (1, 2005): 1-9].

Anatomical studies show that the posterior longitudinal ligamentcontains an abundance of nerve fibers that are thought to convey pain.Posterior longitudinal ligament innervation is most abundant compared tothe posterior annulus of the disc and extends beyond the level of theinvolved disc [EDGAR M A. The nerve supply of the lumbar intervertebraldisc. J Bone Joint Surg Br 89(9, 2007):1135-1139; BOGDUK N, Tynan W,Wilson A S. The nerve supply to the human lumbar intervertebral discs. JAnat 132(1, 1981):39-56; von DURING M, Fricke B, Dahlmann A. Topographyand distribution of nerve fibers in the posterior longitudinal ligamentof the rat: an immunocytochemical and electron-microscopical study. CellTissue Res 281(2, 1995):325-338; McCARTHY P W, Petts P, Hamilton A.RT97- and calcitonin gene-related peptide-like immunoreactivity inlumbar intervertebral discs and adjacent tissue from the rat. J Anat 180(1, 1992):15-24; AHMED M, Bjurholm A, Kreicbergs A, Schultzberg M.Neuropeptide Y, tyrosine hydroxylase and vasoactive intestinalpolypeptide-immunoreactive nerve fibers in the vertebral bodies, discs,dura mater, and spinal ligaments of the rat lumbar spine. Spine 18(2,1993):268-273; KALLAKURI S, Cavanaugh J M, Blagoev D C. Animmunohistochemical study of innervation of lumbar spinal dura andlongitudinal ligaments. Spine 23(4, 1998):403-411; TAKEBAYASHI T,Cavanaugh J M, Kallakuri S, Chen C, Yamashita T. Sympathetic afferentunits from lumbar intervertebral discs. J Bone Joint Surg Br 88(4,2006):554-557; NAKAMURA S I, Takahashi K, Takahashi Y, Yamagata M,Moriya H. The afferent pathways of discogenic low-back pain. Evaluationof L2 spinal nerve infiltration. J Bone Joint Surg Br 78(4,1996):606-612].

The pain signals from the posterior and posterior-lateral annulusfibrosus of the intervertebral disc, as well as the overlying posteriorlongitudinal ligament, are relayed to the brain via a complex network ofnerves. Some of these nerves are sensory branches of the sinuvertebralnerve while others are sympathetic nerves, thus creating a dual patternof innervation. Furthermore, the network of nerves spans regions aboveand below the involved disc, which likely explains the common difficultyof localizing discogenic back pain to a single vertebral level. Thecomplexity of the nerve network is such that it is difficult to identifythe circuits that are involved in the production of pain, and thosecircuits may in any event vary from individual to individual [J. RandyJINKINS. The anatomic and physiologic basis of local, referred, andradiating lumbosacral pain syndromes related to disease of the spine. JNeuroradiol 31(2004): 163-180]. Compounding the complexity is thelikelihood that neuropeptide pools in structures such as the dorsal rootganglion may change in response to mechanical or chemical stresses[GRONBLAD M, Weinstein J N, Santavirta S. Immunohistochemicalobservations on spinal tissue innervation. A review of hypotheticalmechanisms of back pain. Acta Orthop Scand 62(6, 1991):614-622].Plasticity in the components of the central and sympathetic nervoussystem that are involved in the sensation of pain also adds to thecomplexity [KUNER R. Central mechanisms of pathological pain. Nat Med16(11, 2010):1258-1266; SCHLERETH T, Birklein F. The sympathetic nervoussystem and pain. Neuromolecular Med 10(3, 2008):141-147].

Instead of attempting to address all of those mechanisms, an initialembodiment of the invention focuses on the particular goal of reducingthe patient's pain through the enhancement/activation or the blocking ofsignals in sympathetic nerves within the posterior longitudinal ligamentand/or underlying annulus fibrosus. The term sympathetic nerve is usedhere in the conventional sense to mean a postganglionic efferent nervethat uses norepinephrine (noradrenaline) as the primary neurotransmitterto effect a response in the end organ (with the exception of neurons ofsweat glands and chromaffin cells of the adrenal medulla).Notwithstanding the confusingly misleading common informal use of theterm “sympathetic afferents”, all sympathetic nerves are efferent,because afferent fibers of the autonomic nervous system, which transmitsensory information from the internal organs of the body back to thecentral nervous system, are not divided into parasympathetic andsympathetic fibers as the autonomic efferent fibers are. Instead,autonomic sensory information may be conducted by general visceralafferent fibers that may run alongside the efferent fibers (e.g.,sympathetic fibers), travel up to the ganglion where the efferent fibersynapses (e.g., sympathetic ganglion), continue into the sympathetictrunk, and move into the mixed spinal nerve between the division of therami and the division of the roots of the spinal nerve. But the afferentpathway then diverges from the sympathetic efferent pathway, byfollowing the dorsal root into the dorsal root ganglion, where the cellbody of the visceral afferent nerve is located. When someone uses theinformal term “sympathetic afferent” they do not mean that the afferentis actually a sympathetic nerve, but they mean instead that the afferentnerve co-travels with a sympathetic efferent nerve [TAKEBAYASHI T,Cavanaugh J M, Kallakuri S, Chen C, Yamashita T. Sympathetic afferentunits from lumbar intervertebral discs. J Bone Joint Surg Br 88(4,2006):554-557].

Confusion also arises when nerves are stained using acetylcholinesterasehistochemistry, which stains both adrenergic and cholinergic fibers.Investigators who stain nerves using acetylcholinesterase histochemistrywarn that “ . . . acetylcholesterase activity is not an indication for acholinergic nature of neurons. For example, noradrenergic nerve elementsare also stained. Consequently, somato-efferent and pre- andpostganglionic sympathetic, as well as afferent nerve fibers are madevisible” [GROEN G J, Baljet B, Drukker J. Nerves and nerve plexuses ofthe human vertebral column. Am J Anat 188(3, 1990):282-296]. In view ofthe comments in the previous paragraph, the fact that such a stainednerve may be traced to a sympathetic ganglion, or otherwise partlyexhibits an anatomical course that is characteristic of actualsympathetic nerves, does not imply that the stained nerve is asympathetic nerve. Thus, if a nerve in the posterior longitudinalligament is thought to originate from rami communicates at differentlevels of the sympathetic trunk, one may not conclude that the nerve isa sympathetic nerve. Similar confusion may arise if a sympatheticganglion is ablated and that ablation reduces the patient's pain,because the reduction in pain could well be attributed to damage tonerves that co-travel with the sympathetic nerves, rather than to damageto the sympathetic nerves themselves [SCHOTT G D. Visceral afferents:their contribution to ‘sympathetic dependent’ pain. Brain 117 (Pt 2,1994):397-413; KOJIMA Y, Maeda T, Arai R, Shichikawa K. Nerve supply tothe posterior longitudinal ligament and the intervertebral disc of therat vertebral column as studied by acetylcholinesterase histochemistry.I. Distribution in the lumbar region. J Anat 169(1990):237-246; KOJIMAY, Maeda T, Arai R, Shichikawa K. Nerve supply to the posteriorlongitudinal ligament and the intervertebral disc of the rat vertebralcolumn as studied by acetylcholinesterase histochemistry. II. Regionaldifferences in the distribution of the nerve fibres and their origins. JAnat 169(1990):247-255; NAKAMURA S, Takahashi K, Takahashi Y, MorinagaT, Shimada Y, Moriya H. Origin of nerves supplying the posterior portionof lumbar intervertebral discs in rats. Spine (Phila Pa. 1976) 21(8,1996):917-924; SUSEKI K, Takahashi Y, Takahashi K, Chiba T, Yamagata M,Moriya H. Sensory nerve fibres from lumbar intervertebral discs passthrough rami communicates. A possible pathway for discogenic low backpain. Bone Joint Surg Br 80(4, 1998):737-742].

Rather than use acetylcholesterase histochemistry or some othernon-specific staining method, one may instead use tyrosine hydroxylasehistochemistry to demonstrate catecholamines in the efferent sympatheticnerves, or use some other method that is reasonably specific for thesympathetic nerves, e.g., staining for the C-flanking peptide ofneuropeptide Y [Shinji IMAI, Yrjö T Konttinen, Yoshimitsu Tokunaga,Toshihiro Maeda, Sinsuke Hukuda, Seppo Santavirta. Tyrosinehydroxylase-immunoreactive nerve fibres in rat posterior longitudinalligament. Journal of the Autonomic Nervous System 63 (1-2, 1997): 51-60;AHMED M, Bjurholm A, Kreicbergs A, Schultzberg M. Neuropeptide Y,tyrosine hydroxylase and vasoactive intestinalpolypeptide-immunoreactive nerve fibers in the vertebral bodies, discs,dura mater, and spinal ligaments of the rat lumbar spine. Spine (PhilaPa. 1976)18(2, 1993):268-273; von DURING M, Fricke B, Dahlmann A.Topography and distribution of nerve fibers in the posteriorlongitudinal ligament of the rat: an immunocytochemical andelectron-microscopical study. Cell Tissue Res 281(2, 1995):325-338;KALLAKURI S, Cavanaugh J M, Blagoev D C. An immunohistochemical study ofinnervation of lumbar spinal dura and longitudinal ligaments. Spine23(4, 1998):403-411; PALMGREN T, Gronblad M, Virri J, Seitsalo S,Ruuskanen M, Karaharju E. Immunohistochemical demonstration of sensoryand autonomic nerve terminals in herniated lumbar disc tissue. Spine21(1996):1301-1306; PALMGREN T, Gronblad M, Virri J, Kääpä E, KaraharjuE. An immunohistochemical study of nerve structures in the annulusfibrosus of human normal lumbar intervertebral discs. Spine (Phila Pa.1976) 24(20, 1999):2075-2079].

After using tyrosine hydroxylase histochemistry to stain the posteriorlongitudinal ligament (PLL) and annulus fibrosus, the observedsympathetic-specific staining pattern may be interpreted in terms of theanatomy of the PLL and underlying annulus fibrosus. The PLL consists oftwo layers: a deep layer and a superficial layer, and two systems ofinnervations observed in the PLL correspond roughly to the two layers ofthe PLL itself. First, many nerve fibers enter the PLL through thesuperficial layer of the annulus fibrosus. In the deeper layer of thePLL this first nerve fiber network innervates the intervertebral portionof the PLL. Second, in the superficial layer of the PLL, thesinuvertebral nerve bifurcates into ascending and descending branches.These further give rise to transverse branches, which in the midsaggitalregion form a superficial network. The intervertebral portion isinnervated dually by the two networks, but the vertebral portion isinnervated only by the superficial network [IMAI S, Konttinen Y T,Tokunaga Y, Maeda T, Hukuda S, Santavira S. An ultrastructural study ofcalcitonin gene-related peptide-immunoreactive nerve fibres innervatingthe rat posterior longitudinal ligament: a morphologic basis for theirpossible efferent actions. Spine, 22(1997): 1941-1947]. Therefore, whenthe objective is to preferentially stimulate sympathetic nerves withinthe PLL and underlying annulus fibrosus, one should preferably use astimulation method that can do so selectively in regions in which thesympathetic nerves are densest, e.g., to just stimulate nerves in theposterior portion of the annulus fibrosus, or just nerves in the deepPLL, or just nerves in the superficial PLL. Methods for performing thatpreferential stimulation of sympathetic nerves are disclosed in detailbelow. In brief, one uses electrical impedance tomography (EIT) tomeasure the conductivity of the regions containing the nerves, thenchooses the amplitude of voltages applied to the lead's electrodes insuch a way as to maximize an electric field there, which is calculatedusing Laplace's equation that incorporates the EIT data.

As described in detail below, the invention also contemplates thesimultaneous measurement of sympathetic tone and pain in the patient.For example, the sympathetic tone may be measured as a noninvasiveelectrodermal response on the patient's feet, and the pain may bemeasured subjectively using self-reporting or measured objectively usingscalp electrodes with an EEG or P300 evoked potential. The measurementsare made continuously, and it is expected that data will fluctuatespontaneously. For example, sympathetic tone may exhibit spontaneousoscillations with widely varying periodicities that reflect theregulation such variables as blood pressure and temperature, thebest-known of which are Mayer waves. When the sympathetic tone and painmeasurements are made, one may find either a positive or negativecorrelation between them. The correlation may be a cross-correlationthat takes into account any time delays accompanying a change insympathetic tone and the resulting change in the level of pain in thepatient (and vice versa). According to the invention, if there is apositive correlation, one would attempt to inhibit the activity ofsympathetic nerves in the posterior longitudinal ligament and underlyingannulus fibrosus, and if there is a negative correlation, one attemptsto increase the activity of sympathetic nerves in the posteriorlongitudinal ligament and underlying annulus fibrosus. Thus, in theformer case, one endeavors to use electrical stimulation (or other formsof stimulation) to block activity of the sympathetic nerves, i.e.,prevent the initiation or propagation of action potentials in thosenerves, and in the latter case one endeavors to use electricalstimulation to increase activity of the sympathetic nerves, i.e.,promote the initiation and propagation of action potentials in thosenerves. Beyond the Laplace equation method mentioned above thatselectively stimulates sympathetic nerves on the basis of theiranatomical location, preferential electrical stimulation of sympatheticnerves within the posterior longitudinal ligament and the underlyingannulus fibrosus may make use of any method known in the art, such aspreferentially stimulating nerves having axon diameters that most nearlymatch those of the sympathetic nerves, or exploiting the absoluterefractory period of sympathetic nerve axons, or the application ofstimulus blocks [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385;John E. SWETT and Charles M. Bourassa. Electrical stimulation ofperipheral nerve. In: Electrical Stimulation Research Techniques,Michael M. Patterson and Raymond P. Kesner, eds. Academic Press. (NewYork, 1981) pp. 243-295].

According to the present invention, the varying role of the sympatheticnervous system in either suppressing or enhancing pain may be understoodin part in terms of the variable content of adrenoreceptors innonicieptors. As a proposed mechanism, in some nociceptors, subtypes ofalpha-1 adrenoreceptors may predominate, and otherwise, certain subtypesof alpha-2 adrenoreceptors may predominate. Norepinephrine that isreleased from the sympathetic nerves would bind to those adrenoreceptorsand enhance or inhibit the activity of the nociceptors, respectively.According to this proposed mechanism, in order to minimize pain,electrical stimulation of the sympathetic nerves should attempt toinhibit or enhance activity of the sympathetic nerves, therebyinhibiting or enhancing the release of norepinephrine, depending on thereceptor status of the nociceptors that may be inferred from theabove-mentioned simultaneous measurement of sympathetic tone and pain.The role of alpha-1 adrenoreceptors has support in this regard, but onlyfor other types of pain [James N. CAMPBELL, Richard A. Meyer, SrinivasaN. Raja. Is nociceptor activation by alpha-1 adrenoreceptors the culpritin sympathetically maintained pain? APS Journal 1(1, 1992):3-11; DAWSONL F, Phillips J K, Finch P M, Inglis J J, Drummond P D. Expression ofα1-adrenoceptors on peripheral nociceptive neurons. Neuroscience175(2011):300-314; DONELLO J E, Guan Y, Tian M, Cheevers C V, AlcantaraM, Cabrera S, Raja S N, Gil D W. A peripheral adrenoceptor-mediatedsympathetic mechanism can transform stress-induced analgesia intohyperalgesia. Anesthesiology 114(6, 2011):1403-1416]. Thus, this type ofmechanism has been described in connection with disorders such aspancreatic cancer, reflex sympathetic dystrophy, causalgia,posttraumatic neuralgia, phantom limb pain and acute herpes zoster, butnot in connection with discogenic back pain [Ralf BARON and WilfridJanig. Sympathetically maintained pain. Chapter 22. pp. 309-320. In:Pain—Current Understanding, Emerging Therapies, and Novel Approaches toDrug Discovery (Chas Bountra, Rajesh Munglani, and William K. Schmidt,eds.) New York: Marcel Dekker, Inc., 2003].

The proposed role for alpha-2 adrenoreceptor subtypes apparently has nosupport even for other types of pain, because Applicant is unaware ofany situation in which the activation of the sympathetic nervous systemis used as a strategy to reduce pain in a patient [Mick SERPELL. Therole of the sympathetic nervous system and pain. Anesthesia & IntensiveCare Medicine 9(2, 2008):75-78]. In fact, the converse intervention ofattempting to block sympathetic efferent nerves has been a commonapproach in reducing pain, and detractors of that approach say that theblocking may be ineffective or misinterpreted rather thancounterproductive [SCHOTT G D. Visceral afferents: their contribution to‘sympathetic dependent’ pain. Brain 117 (Pt 2, 1994):397-413; VERDUGO RJ, Ochoa J L ‘Sympathetically maintained pain.’ I. Phentolamine blockquestions the concept. Neurology 44(1994):1003-1010; Mitchell B. MAX andIan Gilron. Sympathetically maintained pain: Has the emperor no clothes?Neurology 52(5, 1999): 905-907; Vaughan G. MACEFIELD. A role for thesympathetic nervous system in sympathetically maintained pain? ClinicalNeurophysiology 121(2010): 996-997]. Activation of the sympatheticnerves as a strategy to reduce discogenic back pain is motivated here bythe observation that in patients who are not experiencing pain, thatactivation may prevent pain that that would otherwise occur [SCHLERETHT, Birklein F. The sympathetic nervous system and pain. NeuromolecularMed 10(3, 2008):141-147]. A mechanism that may account for thatobservation is that particular subtypes of alpha-2 adrenoreceptors, suchas the alpha-2C subtype, appear to be anti-nociceptive and may bepresent in afferent nerves [KHASAR S G, Green P G, Chou B, Levine J D.Peripheral nociceptive effects of alpha 2-adrenergic receptor agonistsin the rat. Neuroscience 66(2, 1995):427-432; K. O. ALEY and Jon D.Levine. Multiple receptors involved in peripheral alpha-2, mu, and A1antinociception, tolerance, and withdrawal. The Journal of Neuroscience17(2, 1997):735-744; FAIRBANKS C A, Stone L S, Kitto K F, Nguyen H O,Posthumus I J, Wilcox G L. alpha(2C)-Adrenergic receptors mediate spinalanalgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 300(1,2002):282-290]. During the inflammatory sensitization of the lumbarspine that may co-occur with the development of pain, many changes takeplace in the composition and physiology of afferent receptors, but ifthe anti-nociceptive alpha-2 adrenoreceptors persist for an extendedperiod of time during that sensitization, their binding to thenorepinephrine that is released by sympathetic efferent nerves may stillbe available as a method for reducing pain [KOLTZENBURG M, McMahon S B.The enigmatic role of the sympathetic nervous system in chronic pain.Trends Pharmacol Sci 12(11, 1991):399-402].

As described above, the decision as to whether to attempt to enhance orinhibit the activity of the sympathetic nerves is made according towhether there is a positive or negative correlation (orcross-correlation) between sympathetic tone and pain, in which thesympathetic tone measurement is made so as to correspond to a regionthat would include the lumbar spine. The present invention disclosesadditional methods for assessing the extent to which the regionalsympathetic tone corresponds to the local sympathetic tone within theposterior longitudinal ligament and the underlying annulus fibrosus. Asdescribed in detail below, that assessment makes use of laser Dopplerflowmetry to measure continuously the flow of blood in selectedlocations within the PLL and/or underlying annulus fibrosus. In normalindividuals, noripinephrine released from sympathetic nerves onto alphareceptors in blood vessels causes vasoconstriction. Thus, an increase ordecrease in sympathetic tone would normally result in a decrease orincrease, respectively, in blood flow to the corresponding portion ofthe lumbar region. Consequently, the measurement of changes in bloodflow may normally be used to infer changes in the sympathetic activitythat caused the blood flow changes. However, the situation is morecomplex in tissue that is experiencing inflammation, such that thenormal relation between local sympathetic tone and blood flow may becomedistorted. Therefore, to the extent that the measured local sympathetictone corresponds to the regional sympathetic tone, the latter may beused in analyzing the relation between sympathetic tone and pain.Otherwise, the local sympathetic tone would be used.

The blood flow measurement using laser Doppler flowmetry may also beused to assess the extent to which stimulation of the nerves in the PLLand/or underlying annulus fibrosus, using a particular set ofstimulation parameters (e.g., amplitude, frequency, pulse width, etc.)or waveform type more generally, is either enhancing or inhibiting theactivity of the sympathetic nerves. If the assessment is done in anormal individual, the enhancement or inhibition may be inferred fromwhether the measured blood flow decreases or increases, respectively,following application of the electrical stimulus. Thus, duringenhancement, noripinephrine released from the sympathetic nerves ontoblood vessels causes vasoconstriction and a decrease of blood flow, andduring inhibition, the reduced release of noripinephrine would allow theblood vessels to vasodilate beyond their basal tonic diameters,resulting in increased blood flow. In a patient experiencinginflammation, the magnitude of the blood flow changes may differ fromthose characteristic of a normal individual and conceivably could evenshow an anomalous reversal between vasoconstriction and vasodilation[KOEDA T, Sato J, Kumazawa T, Tsujii Y, Mizumura K. Effects ofadrenoceptor antagonists on the cutaneous blood flow increase responseto sympathetic nerve stimulation in rats with persistent inflammation.Jpn J Physiol 52(6, 2002):521-530]. Even so, the measurement of anychange in blood flow following application of the electrical stimuluswould indicate that the electrical stimulation is having a measurableeffect on the sympathetic nerves. Any accompanying decrease in the levelof pain in the patient could therefore be taken as evidence that theelectrical impulses to the sympathetic nerves at least partially relievethe pain, for those stimulation parameters, or waveform type moregenerally. In this embodiment of the invention, the most effectiveparameters for electrical stimulation may change over time by virtue ofthe fact that the inflammation in the patient's lumbar spine is runningits course independently, such that changes in receptor compositionwithin the nociceptors would necessitate using different optimalstimulation parameter values (or waveform types more generally) thatcorrespond to those changes.

Electrical stimulation of sympathetic nerves has been disclosedpreviously, but not to postganglionic efferent nerves in the PLL forpurposes of discogenic back pain treatment. For example, REZAIstimulated the lumbar sympathetic ganglia to inhibit nerves there, inorder to treat conditions other than lumbar back pain [U.S. Pat. No.8,046,075, entitled Electrical stimulation of the sympathetic nervechain, to REZAI; U.S. Pat. No. 6,438,423, entitled Method of treatingcomplex regional pain syndromes by electrical stimulation of thesympathetic nerve chain, to REZAI]. U.S. Pat. No. 7,239,912, entitledElectric modulation of sympathetic nervous system, to DOBAK, disclosesthe use of electrical stimulation to modulate activity of thesympathetic nervous system, but it is directed to the treatment ofobesity and is unrelated to the treatment of pain. Pending applicationU.S. Ser. No. 13/458,697 published as US20120277839, entitled Selectivestimulation to modulate the sympathetic nervous system, to KRAMER et al.discloses stimulating a dorsal root ganglion upstream of at least oneganglion of the sympathetic nerve chain, but it is not concerned withdiscogenic back pain. U.S. Pat. No. 7,890,166, entitled Regionaltherapies for treatment of pain, to HERUTH et al., teaches the infusionof drugs in conjunction with the implantation of electrodes in tworegions of the body, along with electrical stimulation of the tworegions limited to two separate low and high frequencies, in which thedrug may be the alpha2-adrenergic agonist clonidine. This differs fromthe present invention because the disclosure here does not involveinfusion of any drug, much less infusion of a drug that specificallyaffects sympathetic nerves, and the use of electrodes is directed here aspecific single region (viz., lumbar posterior longitudinal ligament andunderlying annulus fibrosus) that can involve a wide range offrequencies and waveforms that specifically modulate sympathetic nerves.U.S. Pat. No. 7,769,442, entitled Device and method for inhibitingrelease of pro-inflammatory mediator, to SHAFER and U.S. Pat. No.7,418,292, entitled Device and method for attenuating an immuneresponse, to SHAFER, both pertain to electrically stimulating asympathetic nerve, particularly the splenic nerve, to modulate an immuneresponse, but they do not pertain to treatment of pain, much lessdiscogenic lumbar back pain.

The sympathetic mechanisms that are disclosed here are also in contrastto the disclosure in pending later-priority application No. U.S. Ser.No. 13/469,880, with publication No. US 20120290059, entitled System andmethod for electrical modulation of the posterior longitudinal ligament,to BRADLEY. That application does not disclose electrical stimulation ofsympathetic nerves in connection with the treatment of discogenic pain.In fact, in the course of prosecuting that application, BRADLEY teachesagainst a role for sympathetic nerves in the transmission of disc pain,by citing as authority the following publication: BOGDUK N. Theinnervation of the lumbar spine. Spine 8(3, 1983):286-293. Thatpublication states that “The topographic association between thesympathetic nervous system and the nerves supplying the intervertebraldiscs does not invite the conclusion that these discs are innervated bythe autonomic nervous system . . . . Indeed, clinical studies haveexcluded a role for the sympathetic nervous system in the mediation ofback pain.” Others investigators also teach away from a role for thesympathetic nervous system in the mediation of pain [SCHOTT G D.Visceral afferents: their contribution to ‘sympathetic dependent’ pain.Brain 117 (Pt 2, 1994):397-413; VERDUGO R J, Ochoa J L ‘Sympatheticallymaintained pain.’ I. Phentolamine block questions the concept. Neurology44(1994):1003-1010; Mitchell B. MAX and Ian Gilron. Sympatheticallymaintained pain: Has the emperor no clothes? Neurology 52(5, 1999):905-907; Vaughan G. MACEFIELD. A role for the sympathetic nervous systemin sympathetically maintained pain? Clinical Neurophysiology 121(2010):996-997]. From the point of view of such teaching away from thepresently disclosed mechanism, it is disputable whether reversibleelectrical stimulation of sympathetic nerves within or near theposterior longitudinal ligament, as taught here, could in principleaffect the pain being experienced by the patient.

In summary, the disclosure above is consistent with at least thefollowing mechanisms by which reversible electrical stimulation of thenerves in the posterior longitudinal ligament and underlying annulusfibrosus may reduce discogenic back pain:

(1) The stimulation may cause the nerves in the posterior longitudinalligament and/or posterior annulus fibrosus to increase the mechanicalforce threshold above which the nerves generate an action potential.Thus, if there are fewer nociceptive signals from these nerves, thesensation of pain may decrease. (2) The stimulation may cause thesympathetic nerves in the posterior longitudinal ligament and/orposterior annulus fibrosus to suppress the transmission of actionpotentials originating in the nociceptive nerves in the posteriorlongitudinal ligament and/or posterior annulus fibrosus. Under normalconditions, the sympathetic nervous system suppresses pain by thismechanism, and the electrical stimulation of the present invention maycause the sympathetic nerves to behave normally. On the other hand,under abnormal conditions, the sympathetic nervous system enhances thetransmission of action potentials originating in nociceptive nerves. Inthat case, the electrical stimulation may cause a decreased enhancementby sympathetic nerves of the transmission of action potentialsoriginating in nociceptive nerves in the posterior longitudinal ligamentand/or posterior annulus fibrosus. (3) The stimulation may cause thenerves in the posterior longitudinal ligament and/or posterior annulusfibrosus to decrease their content of substance P and/orvasoactive-intestinal peptide and/or calcitonin-gene-related peptide.These chemicals are associated with inflammatory processes and pain, andtheir loss may reverse the inflammatory processes and pain.

For some patients, reversible stimulation of the nerves of the posteriorlongitudinal ligament and underlying annulus fibrosus may beunsuccessful in significantly reducing lower back pain (electrically orby other stimulation modalities that are disclosed below). For thosepatients, the stimulator lead and any implanted pulse generator may beremoved. However, before they are removed, a final attempt may be madeto reduce the back pain, this time by stimulating the nerves in anattempt to produce irreversible damage to the nerves. It is understoodthat the term “irreversible” is not synonymous with “permanent,” becauseonce the nerves are destroyed, new nerve fibers may eventually grow backinto the locations that had been occupied by the destroyed nerve fibers.Consequently, if the irreversible damage to the offending nerves issuccessful, it may be prudent to leave the stimulator in place for anextended period of time, in the event that newly ingrown nerves maythemselves eventually need to be treated or irreversibly damaged by thedevices of the invention.

As noted above in the background section, methods and devices have beenproposed for irreversibly ablating nerves in the posterior longitudinalligament, in the following patents or applications: U.S. Pat. No.6,772,012 and U.S. Pat. No. 7,270,659, entitled Methods forelectrosurgical treatment of spinal tissue, to RICART et al; U.S. Pat.No. 7,331,956, entitled Methods and apparatus for treating back pain, toHOVDA et al.; and abandoned application U.S. Ser. No. 11/105,274,corresponding to publication No. US20050261754, entitled Methods andapparatus for treating back pain, to WOLOSZKO et al. All of thosemethods are intended to affect the region of the posterior longitudinalligament (among other regions) irreversibly, through the application ofjoule heating. The heating is due to the application of radiofrequencyenergy (typically 100 kHz to 2 MHz) to the offending area after applyingan electrode there. Electrodes of the present invention could inprinciple also be used for that purpose, although it is understood thatelectrodes for thermal ablation are best designed specifically for thatpurpose [Yongmin K I M, H. Gunter Zieber, and Frank A. Yang. Uniformityof current density under stimulating electrodes. Critical Reviews inBiomedical Engineering 17(1990, 6): 585-619]. The mechanism by which thedelivered radiofrequency energy heats and ablates the tissue attemperatures generally at or above 45 C is well understood [HABASH R W,Bansal R, Krewski D, Alhafid H T. Thermal therapy, part 1: anintroduction to thermal therapy. Crit Rev Biomed Eng 34(6,2006):459-489; DIEDERICH C J. Thermal ablation and high-temperaturethermal therapy: overview of technology and clinical implementation. IntJ Hyperthermia 21(8, 2005): 745-753; HAVEMAN J, Van Der Zee J, WondergemJ, Hoogeveen J F, Hulshof M C. Effects of hyperthermia on the peripheralnervous system: a review. Int J Hyperthermia 20(4, 2004):371-391].

However, it is possible to damage tissue by electrical stimulationmechanisms other than heating, and those are the preferred mechanismsthat are used in the present invention [LEE R C, Zhang D, Hannig J.Biophysical injury mechanisms in electrical shock trauma. Annu RevBiomed Eng 2(2000):477-509]. In particular, nonthermal irreversibleelectroporation may be used to damage tissue [DAVALOS R V, Mir I L,Rubinsky B. Tissue ablation with irreversible electroporation. AnnBiomed Eng 33(2, 2005):223-231; RUBINSKY B. Irreversible electroporationin medicine. Technol Cancer Res Treat 6(4, 2007):255-260]. Becausenonthermal irreversible electroporation permeabilizes and damages a cellmembrane without causing thermal damage, the integrity of molecules suchas collagen and elastin in the target region is generally preserved.

In electroporation, a pulse of electric field is generated between twoelectrodes (preferably first with one polarity, then with the reversepolarity). The damage to cells by electroporation is a function of theelectric field strength, the pulse duration, and the number of pulses.To damage the cells, the field should generally be greater than 680volts per cm (typically 1000 volts per cm), the pulse duration should be0.5-10 millisec (typically 1.0 millisec) separated by 10 sec to minimizethe likelihood of Joule heating. However, muscle and nerve cells mightbe damaged by electric fields as small as 60 V/cm, so in the presentinvention the electrical field is applied stepwise with increasing V/cmuntil the intended therapeutic effect is achieved. Damage will occurfirst to non-myelinated nerves, because the myelin of myelinated nervesprotects those nerves [DANIELS C, Rubinsky B. Electrical field andtemperature model of nonthermal irreversible electroporation inheterogeneous tissues. J Biomech Eng 131(7, 2009): 071006, pp 1-12;DAVALOS R V, Otten D M, Mir L M, Rubinsky B. Electrical impedancetomography for imaging tissue electroporation. IEEE Trans Biomed Eng51(5, 2004):761-767; GRANOT Y, Rubinsky B. Methods of optimization ofelectrical impedance tomography for imaging tissue electroporation.Physiol Meas 28 (10, 2007):1135-1147; LINDERHOLM P, Marescot L, Loke MH, Renaud P. Cell culture imaging using microimpedance tomography. IEEETrans Biomed Eng 55(1, 2008):138-146]. However, there is an abundance ofnon-myelinated nerves relative to myelinated nerves in the annulus andposterior longitudinal ligament, so the nerve damage will be significant[McCARTHY P W, Petts P, Hamilton A. RT97- and calcitonin gene-relatedpeptide-like immunoreactivity in lumbar intervertebral discs andadjacent tissue from the rat. J Anat 180 (1, 1992):15-24]. One ablativemethod of the present invention is to perform irreversibleelectroporation with relatively low electric fields to spare themyelinated nerve fibers, then resume reversible stimulation toneuromodulate their activities as in the preferred embodiment of thepresent invention. If the resumed reversible stimulation is notsuccessful in reducing the back pain, then irreversible electroporationcan be repeated with a higher electric field to ablate all of theoffending nerves. As with the reversible stimulation, intra-operativeelectrophysiologic monitoring is performed in order to assure that theablation does not harm the thecal sac and nerves contained therein[Thomas N. PAJEWSKI, Vincent Arlet and Lawrence H. Phillips. Currentapproach on spinal cord monitoring: the point of view of theneurologist, the anesthesiologist and the spine surgeon Eur Spine J16(Suppl 2, 2007): 115-129; MALHOTRA, Neil R and Shaffrey, ChristopherI. Intraoperative electrophysiological monitoring in spine surgery.Spine 35(25, 2010):2167-2179].

The electronics of a conventional 0 to 10V pulse generator is adapted toproduce such higher voltage electroporation pulses [Abbas POURZAKI andHossein Mirzaee. New high voltage pulse generators. Recent Patents onElectrical Engineering 2(2009):65-76]. To irreversibly electroporate(ablate) the entire surface area covered by the lead, pulses may begenerated pairwise between many of the electrodes. An advantage oflimiting the electroporation pulses to pairs of electrodes within thelead is that it minimizes any pain that the patient may experience fromthe pulses. If two electrodes of the lead in FIG. 7A are separated by0.5 cm, then typically a 1 millisecond pulse of 500 V is applied betweenthem. The closer that the electrodes are to one another, then thesmaller the applied voltage must be in order to damage the underlyingnerve. If the parameters that are used do not reduce the pain, the pulseduration is increased, the voltage is increased (up to the limit of thepulse generator, typically 1000 V), and/or the pulsation continues every10 seconds until the pain is reduced.

If the electroporation is not successful in significantly reducing thepain, the stimulation parameters may be changed to allow joule heatingand dielectric heating of proteins to be additional mechanisms ofdamage. Thus, in the preferred embodiment of electroporation ablation,pulses are separated by at least 10 seconds to minimize the likelihoodof damage from joule heating (i.e., a stimulation frequency of less thanor equal to 0.1 Hz). This constraint may then be relaxed such thatpulses are delivered at higher frequencies, with or without simultaneousadjustment of the stimulation voltage. As the frequency is increasedgradually from 0.1 Hz to 10 kHz, joule heating will increasinglycontribute to the mechanism of ablation, provided that the amplitude'svoltage is set for a long enough time to a value greater than a voltagethat may be used for reversible stimulation. Above about 10 kHz, thedielectric heating of proteins will also contribute as a mechanism ofablation, wherein cellular proteins denature and become unable tofunction normally. This is because at those higher stimulationfrequencies, the cell membrane is no longer an effective barrier to thepassage of electrical current, and capacitive coupling of power acrosseach cell membrane permits the passage of current into the cytoplasm[LEE R C, Zhang D, Hannig J. Biophysical injury mechanisms in electricalshock trauma. Annu Rev Biomed Eng 2(2000):477-509]. Such ablation bydielectric heating of proteins may be attempted up to the highest pulsefrequency that can be generated by the pulse generator, typically 20 kHzto 50 kHz. At such frequencies, one of the lead electrodes at a time mayserve as an active electrode, and current is collected in a much largerreturn electrode (dispersive electrode) which may comprise many of theremaining electrodes connected together electrically to the case of thepulse generator, or which may be a separate dispersive electrode if theablation is being attempted during surgery prior to removal of thepaddle lead [Yongmin K I M, H. Gunter Zieber, and Frank A. Yang.Uniformity of current density under stimulating electrodes. CriticalReviews in Biomedical Engineering 17(1990, 6): 585-619].

In order to effect a controlled thermal ablation, one or more smalltemperature sensor is mounted on the electrode side of the lead (e.g.,thermocouple, thermistor, silicon band gap temperature sensor,resistance temperature detector or other such sensor known in the art)and connected to the pulse generator, which makes a time vs. temperaturereadout available to the care-giver through the programmer. A thermaldose that is effective in ablating the nerves is applied, which is afunction of the measured temperature and duration of heating [HABASH RW, Bansal R, Krewski D, Alhafid H T. Thermal therapy, part 1: anintroduction to thermal therapy. Crit Rev Biomed Eng 34(6,2006):459-489; DIEDERICH C J. Thermal ablation and high-temperaturethermal therapy: overview of technology and clinical implementation. IntJ Hyperthermia 21(8, 2005): 745-753; HAVEMAN J, Van Der Zee J, WondergemJ, Hoogeveen J F, Hulshof M C. Effects of hyperthermia on the peripheralnervous system: a review. Int J Hyperthermia 20(4, 2004):371-391]. Aswith the reversible stimulation and electroporative ablation,intra-operative electrophysiologic monitoring is performed in order toassure that the thermal ablation does not harm the thecal sac and nervescontained therein. A significant difference between such thermalablation and the methods disclosed in the above-cited patents and patentapplications to RICART et al, HOVDA et al, and WOLOSZKO et al. is thatin the present invention, the insulation of the lead (62 in FIG. 7)serves not only as electrical insulation, but also as thermalinsulation, thus making it possible to direct accumulated applied heatto the posterior longitudinal ligament and posterior annulus fibrosus,and yet shield substantially all of the cauda equina, thecal sac andnerve roots from that heat. For extra thermal protection, an extra layerof thermal insulation (e.g., biocompatible ceramic foam) may be used tocoat the side of the lead that is placed nearest the cauda equina.

In addition to the use of reversible and irreversible electricalstimulation to modulate, inhibit or damage the function of nerves in theposterior longitudinal ligament and/or in the underlying annulusfibrosus, the present invention discloses the use of additionalstimulation modalities. They comprise the reversible or irreversiblestimulation of the nerves using light, the reversible or irreversiblestimulation of the nerves using mechanical vibration, and reversible orirreversible changes made to the functioning of the nerves throughcooling. These different stimulation modalities may be appliedseparately or together. Furthermore, as described below, each of thesemodalities (electrical, light, vibration, and cold) may be applieddiagnostically to evoke potentials for purposes of preliminarilyevaluating the pathophysiology of the patient's back pain, which maythen be used to select parameters of the reversible or irreversiblestimulation by any or all of the types of applied energy.

In one aspect of the invention, ultraviolet, visible, or infrared lightmay be used to stimulate nerves within the posterior longitudinalligament or underlying annulus fibrosus. The light source will generallybe either a laser diode or an LED. The purpose of stimulation of thenerves with light can be to induce either reversible or irreversibleeffects. Generally, ultraviolet light is used to produce irreversibledamage, and light with longer wavelengths (e.g., infrared) is used toproduce reversible effects, although brief exposure to ultraviolet lightmay be reversible and extended exposure to light with longer wavelengthsmay produce damage. Although the primary use of the light source isstimulation of the nerves, it is understood that the light may also beused to illuminate a field of view for an ultra-miniature camera that isbuilt into the lead to guide implantation, especially a percutaneouslead with the camera positioned near its distal tip. The wavelength ofthe light source may be selected with this in mind, although for someimagers their response is nearly invariant with respect to wavelength[David G. STORK and Patrick R. Gill. Lensless ultra-miniature CMOScomputational imagers and sensors. pp. 186-191 In: Proceedings, SeventhInternational Conference on Sensor Technologies and Applications(SENSORCOMM 2013), held 25-31 Aug. 2013 in Barcelona, Spain. Red Hook,N.Y.: Curran Associates, Inc., 2013]. Another secondary application ofthe laser diode is its use to measure blood flow in the tissue that isilluminated by the light, using laser Doppler flowmetry, as describedlater in connection with the measurement of sympathetic tone. The laserDoppler device may also be used to measure tissue vibrations that arecaused by the vibrator that is described later.

The laser diode or LED may be mounted on the stimulation lead device,with attached wires connecting the device to its controller. Thecontroller is generally housed in the same housing used to contain thecontrol circuitry for electrical stimulation, so in what follows theterm “pulse generator” is used to describe all such control circuits.Alternatively, the laser diode or LED light source may be situatedwithin the housing of the pulse generator, with the light transmittedvia optical fibers that terminate on the stimulation lead device [U.S.Pat. No. 8,701,675, entitled Laser treatment for CNS injury, to SCHENKERet al., which describes leads having a diameter of about 3 to 6 mm]. Thelight that emerges from either the lead-mounted light source or theoptical fibers is then directed to the posterior longitudinal ligamentand/or underlying annulus fibrosus, when the lead device is implantedinto the anterior epidural space. The area of light coverage isdetermined by the number of optical elements on the lead, as well as thelenses, mirrors and diffusers used to terminate those optical elements.Generally, the lenses, mirrors and diffusers will be selected tomaximize the area of tissue that is stimulated with the light. The depthof penetration of the light into the tissue depends on its wavelength,with light at some infrared wavelengths being able to penetrate acentimeter or more into the tissue.

Direct mounting of the light source into the lead device has theadvantage of simplicity, such that all connections between the lead andpulse generator use electrical wires. However, the number of presentlyavailable light sources that are sufficiently small (preferably lessthan about 3 mm in diameter) to be mounted advantageously in apercutaneous lead is relatively limited. By way of example, theCSL701/801 series of LEDs from ROHM Semiconductor measure 2.4 mm×2.9mm×3.1 mm, and the Model DL 7891SX 780 nm diode laser from CreativeTechnology has a 3.3 mm diameter [ROHM Semiconductor U.S.A., LLC 2323Owen Street, Santa Clara, Calif. 95054; Creative Technology Lasers 180Alderwood Road, Walnut Creek, C A 94598-1042]. To keep the diameter ofthe lead device as small as possible, unnecessary portions of the lightsource may be grinded, milled, sanded, and/or polished before assemblyof the lead device. Somewhat larger light sources might be mounted intoa paddle lead, such as the Model RLU4116E ultraviolet laser diode fromRoithner LaserTechnik, which has a more standard diameter of 5.6 mm[Roithner LaserTechnik GmbH. Wiedner Hauptstrasse 76, Vienna, Austria.Nov. 29, 2012. pp. 1-4]. Even so, to keep the thickness of the paddlelead device as small as possible, unnecessary portions of the lightsource may be grinded, milled, sanded, and polished before assembly ofthe lead device.

However, there are advantages to situating the light source within thehousing of the pulse generator, with the light transmitted via opticalfibers that terminate on the stimulation lead device. First, thatpermits the use of a much wider range of available light source sizes[Laser Diode catalog. Roithner LaserTechnik GmbH. Wiedner Hauptstrasse76, Vienna, Austria. Jun. 26, 2014. pp. 1-119]. Second, passive oractive fiberoptic combiners and splitters may be used to direct lightfrom a single light source to multiple locations on the lead device, andmultiple light sources may be used to illuminate a single location onthe lead device. In the latter case, the multiple light sources may havedifferent wavelengths, and the user may decide to use any or all ofthose sources at a particular instant. By way of example, the fiberopticcombiner and splitter may be in the shape of a Y and have fused fiberelements, in which light applied to the base of Y appears at the twoarms at the top of the Y, or two light sources applied to the two toparms of the Y cause light from both sources to combine at the base ofthe Y. If the Y is inverted and is attached to a non-inverted Y, suchthat the inverted and non-inverted Ys are attached at their bases, twolight sources may be used as input to the arms of one of the Ys, and thecombined output would appear in both arms of the other Y. Thus, when oneor the other light source is turned on, its output would appearsimultaneously at two locations of the combiner/splitter, allowing theoperator to select the light source (e.g., wavelength) at more than onelocation on the lead. It is contemplated that such a splitting/combiningdesign is to be used for many more than two sites on a lead and for morethan two selectable light sources (i.e., using more complicatedgeometries than a Y).

The light source that is selected depends on the effect that one isattempting to produce. Much is known about the interaction of light withtissue, although relatively few investigations have been concerned withthe effects of light specifically on nerves [Kendric C. SMITH. Laser andLED photobiology. Laser Therapy 19.2 (2010):72-78]. Many of the earlyapplications of light therapy were intended to damage cells usingultraviolet light, including nerves. Ultraviolet light induces adecrease in membrane sodium permeability, leading to membrane injury inthe nerve [Philip E. HOCKBERGER. A history of ultraviolet photobiologyfor humans, animals and microorganisms. Photochemistry and Photobiology,76(6, 2002):561-579]. As a result, free nerve endings are lost[RODRIGUEZ A L, Stefani F S, de Oliveira Praes C E, Piaceski A, OliveiraM P, Martins P, da Silva V D, Bonorino C, Bauer M E. Effects ofultraviolet radiation on human cutaneous nerve fibres. Cell Prolif 42(4,2009):562-567]. Other damage may be done to nucleic acids within thenerve cell through photo-oxidation, including DNA damage. Thesemechanisms may involve the absorption of light by endogenousphotosensitizers, followed by the chemical reactions that ultimatelyresult in the cellular damage [WONDRAK G T, Jacobson M K, Jacobson E L.Endogenous UVA-photosensitizers: mediators of skin photodamage and noveltargets for skin photoprotection. Photochem Photobiol Sci 5(2,2006):215-237].

If one is attempting to use ultraviolet light to damage the nerve cellsin the posterior longitudinal ligament and underlying annulus fibrosus,one may enhance the effect with the use of a photosensitizer that isadministered to the patient. In particular, one may use psoralen plusUV-A light (PUVA) therapy. For example, using this method 30 mg of theoral psoralen derivative methoxsalen is administered to the patient 75minutes before ultraviolet light from the lead is administered to thepatient. The ultraviolet light is then administered for typically 5-15minutes, during which time the effect on the patient's back pain ismeasured. The entire procedure is performed in a darkened room having noextraneous source of ultraviolet light, so that physiological effectsare limited to the immediate vicinity of the lead, with the lead itselfshielding the thecal sac and nerve roots from exposure to the light. Thepatient remains in a light-protected environment for up to 8 hoursthereafter, considering that the half-life of psoralen compounds is onthe order of 2 hours.

Stimulation of the nerves in the posterior longitudinal ligament andunderlying annulus fibrosus may also make use of wavelengths that areintended to produce reversible effects that reduce pain, which has beeninvestigated in the field of low level light therapy. The wavelengths inthose applications are generally in the infrared [Ying-Ying HUANG, AaronC.-H. Chen, James D. Carroll and Michael R. Hamblin. Biphasic doseresponse in low level light therapy. Dose-Response 7(2009):358-383;Michael R HAMBLIN and Tatiana N Demidova. Mechanisms of Low Level LightTherapy. Proc. of SPIE 6140(2006): 614001, pp. 1-12; CHUNG H, Dai T,Sharma S K, Huang Y Y, Carroll J D, Hamblin M R. The nuts and bolts oflow-level laser (light) therapy. Ann Biomed Eng 40(2, 2012):516-533;HASHMI J T, Huang Y Y, Osmani B Z, Sharma S K, Naeser M A, Hamblin M R.Role of low-level laser therapy in neurorehabilitation. PM R 2(12 Suppl2, 2010):5292-305]. A very useful aspect of this embodiment of theinvention is its ability to potentially reduce inflammation,independently of light-induced effects on the nerves that are related totheir ability to initiate and propagate action potentials.

It is contemplated that stimulation of the nerves with light may also beperformed in conjunction with the stimulation of those nerveselectrically, with mechanical vibration, and/or with the modulation oftemperature. DUKE et al. suggested that it is beneficial to combinelight and electrical stimulation, but combinations of the otherstimulation modalities apparently have not been heretofore disclosed[DUKE A R, Cayce J M, Malphrus J D, Konrad P, Mahadevan-Jansen A, JansenE D. Combined optical and electrical stimulation of neural tissue invivo. J Biomed Opt 14(6, 2009):060501, pp. 1-3].

In another aspect of the present invention, the nerves of the posteriorlongitudinal ligament and/or underlying annulus fibrosus are subjectedto mechanical energy in the form of vibrations. Investigationsconcerning the effect of mechanical vibration on back pain have givencontradictory results. Low frequency vibrations that are encountered inthe workplace, particularly vibrations in the range of 2 to 11 Hz nearthe resonant frequency of the spine, have been shown to increase therisk of disc-related back pain [Taryn E. HILL, Geoffrey T. Desmoulin,Christopher J. Hunter. Is vibration truly an injurious stimulus in thehuman spine? Journal of Biomechanics 42 (2009): 2631-2635]. Vibration athigher frequencies up to 200 Hz for as little as 10 minutes have beenshown to have an effect on the expression of extracellular matrix genesin tissue of the spine, particularly if the vibration amplitude issufficiently high. Nerve damage caused by vibration may result inchanges in gene expression even after the vibration has stopped, in aso-called conditioning lesion that may lead to re-growth of the damagednerve [WIDERBERG A, Bergman S, Danielsen N, Lundborg G, Dahlin L B.Nerve injury induced by vibration: prevention of the effect of aconditioning lesion by D600, a Ca2+ channel blocker. Occup Environ Med54(5, 1997):312-315]. Consequently, in the present invention, ifvibration is being used initially to deliberately damage the nervescausing pain, subsequent vibration may be applied to prevent theregeneration of those pain-causing nerves.

On the other hand, vibration in the range of 80-120 Hz with adisplacement of up to 5 mm has also been shown to reduce self-reportedneck pain, although the vibrations were directed to whole vertebrae, notto particular nerves [DESMOULIN G T, Yasin N I, Chen D W. Spinalmechanisms of pain control. Clin J Pain 23(2007):576-585]. Mechanicalvibrations have also been directed to the treatment of low back pain[LUNDEBERG T, Nordemar R, Ottoson D. Pain alleviation by vibratorystimulation. Pain 20(1, 1984):25-44; ANONYMOUS editor. Vibration therapyfor pain. Lancet. Jun. 20, 1992:1513]. However, none of thoseapplications of vibration have been performed invasively, none usedfrequencies greater than 400 Hz, and none were directed specifically tonerves within the posterior longitudinal ligament or the underlyingannulus fibrosus.

Sub-ultrasonic implantable vibration devices have been disclosed fortreating spinal pain, but by stimulating nerves only indirectly viaconduction of vibrations through bone in the spine [U.S. Pat. No.8,657,765, entitled Analgesic implant device and system, to ASFORA].Direct mechanical vibration of spinal soft tissue containing nervesapparently has not been disclosed heretofore. Furthermore, in thepresent invention, the device causing the vibration is intended to bemounted on, or integral to, the lead that is inserted into the anteriorepidural space of the patient. The vibration devices disclosed by ASFORAare far too large for mounting in or on a stimulation lead, because theyare shown to be implanted in a space between spinous processes of avertebra. More suitably sized vibration devices are the ones used insmartphones [ShreHarsha R A O. High-definition haptics: Feel thedifference! Texas Instruments Analog Application Journal. 3Q2012:29-32]. However, such devices, e.g., piezo actuators, are limitedin the frequency range over which they operate. Nevertheless, electricmotors, solenoid vibration devices, etc., that vibrate over a largerrange of frequencies and that also have suitably small sizes might bedesigned to fit on or in a lead.

In the present application, in a preferred embodiment, the vibrationdevice is adapted from an acoustic speaker (receiver) that is designedfor very small in-the-ear-canal hearing aids. For example, theWBFK-23990-000 hearing aid receiver that is available from KnowlesElectronics (1151 Maplewood Drive, Itasca, Ill. 60143) is an undamped,tubeless magnetic balanced armature receiver that operates over afrequency range of about 10-10,000 Hz and has a size of 5 mm×2.73mm×1.93 mm. The speaker is placed with its long axis within the body ofthe stimulator lead, with one end connected to two wires that supplypower and signals (via the pulse generator) and with the other end atwhich sound vibrations appear either contiguous with the body of thelead (to vibrate the lead itself), or attached to a small 45 degreeacoustic mirror to direct the sound vibrations perpendicular to the longaxis of the lead into an acoustic membrane touching the tissue. Theacoustic mirror may be a triangular piece of steel with a width governedby the width of the speaker, attached at its lowest edge to the speakerand with a diaphragm acoustic membrane stretched from the top of thetriangle to the speaker, with the membrane made of a strong butwaterproof flexible material such as boPET, beryllium or titanium.Alternatively, the diaphragm of the speaker itself may be placed incontact with the tissue that is to be vibrated, which would involve amodification of the speaker, but that would also reduce its size [MeadC. KILLION. Hearing aid transducers. Chapter 166, In: Encyclopedia ofAcoustics, Malcolm J. Croker, ed. New York: John Wiley and Sons, 1997,pp. 1979-1990].

The frequency and amplitude of the vibration may be selected by varyingthe corresponding electrical signal that drives the speaker. Once thelead device is implanted, the frequency and amplitude of the vibrationsare varied systematically, and the effect on the patient's pain ismeasured. Short-term vibration is expected to cause reversible effects,but long-term exposure to vibration may cause irreversible effects. Forexample, if the vibration amplitude is set at the equivalent of 85 dBcontinuously for several hours, the nerves may become irreversiblydamaged. The movement of the vibrated tissue itself may be monitoredusing the laser Doppler flowmeter device that is described below,wherein the tissue vibration would otherwise be regarded as a movementartifact from the point of view of flowmetry.

Vibration damping material is applied to the side of the lead oppositethe vibration-producing device, in order to prevent mechanical damage tothe thecal sac. As noted earlier, that side of the lead may be coatedwith ceramic foam as a thermal insulator. Ceramic foams can be made in away that is similar to the creation of polyurethane foams, with opencell walls forming reticulated channels through the foams, therebyacting as sound and vibration dampers, as well as thermal insulators[Jorge P. ARENAS, and Malcolm J. Crocker. Recent Trends in PorousSound-Absorbing Materials. Sound & Vibration. Jul. 2010: 12-17].

It some embodiments, the mechanical vibrations are appliedsimultaneously with electrical or other modes of stimulation [GUIEU R,Tardy-Gervet M, Roll J. Analgesic effects of vibration andtranscutaneous electrical nerve stimulation applied separately andsimultaneously to patients with chronic pain. Can J Neurol Sci.18(1991):113-119]. In the present invention, the frequencies ofmechanical vibration and electrical stimulation (or light stimulation)are preferably set to be a multiple of one another, in order to enhanceone another's effect. The vibration may also be combined with variationof temperature as follows. In Reynaud's phenomenon, a hyper-activationof the sympathetic nervous system causes extreme vasoconstriction of theperipheral blood vessels that affects the fingers. It may be producedwhen vibration is absorbed, causing mechanical damage to blood vesselsand regulatory nerve elements. When exposed to cold temperatures, theblood supply then becomes markedly reduced. This phenomenon is not knownto occur in the disc, but according to the present invention, it may beinduced there first by applying vibrations to nerves within theposterior longitudinal ligament and underlying annulus fibrosus, andthen by reducing the local temperature there, so as to evokeoversensitivity to cold. In patients who are successfully treated bythat method, the effect will be numbness or paresthesia, withoutproducing pain.

In another aspect of the invention, the cooling of nerves in theposterior longitudinal ligament and/or in the underlying annulusfibrosus is used to modulate or inhibit the activity of those nerves.The cooling may result in reversible or irreversible changes in thenerves, depending on the way in which the cooling is applied. Thecooling may also be performed in conjunction with other stimulationmodalities, including electrical, mechanical-vibration, and lightstimulation, in which the cooling of even a few degrees alters theresponse of the cells to those other stimulation modalities.

It has long been known that the conduction of myelinated nerves iscompletely but reversibly blocked at 5 to 7 degrees C. At about 4degrees C., the smaller C fibers are also blocked. After 15 minutes ofcooling, it may take an hour for the nerve blocking effect to reverse[D. N. FRANZ and A. Iggo. Conduction failure in myelinated andnon-myelinated axons at low temperatures. J Physiol 199(2, 1968):319-345; John E. SWETT and Charles M. Bourassa. Electrical stimulationof peripheral nerves. Chapter 10, pp. 244-295. In: ElectricalStimulation Research Techniques (Michael M. Patterson and Raymond P.Kesner, eds). New York: Academic Press, 1981].

Interpretation of the changes that occur following nerve cooling iscomplicated by circulatory changes that may also accompany cooling. Suchchanges may be monitored using the laser Doppler flowmeter that isdescribed below. Furthermore, even though the electrophysiology of thenerve appears to be normal after a cooling block has reversed, themicroanatomy of the nerve may have been altered [BASBAUM C B. Inducedhypothermia in peripheral nerve: electron microscopic andelectrophysiological observations. J Neurocytol 2(2, 1973):171-187; JIAJ, Pollock M. The pathogenesis of non-freezing cold nerve injury.Observations in the rat. Brain 120 (Pt 4, 1997):631-646; JIA J, PollockM. Cold nerve injury is enhanced by intermittent cooling. Muscle Nerve22(12, 1999):1644-1652]. Nevertheless, focal cooling of the brain to arange of temperatures 5-25 C, in order to prevent epilepsy, has beenperformed successfully in individual animals over a period of manymonths without significant complications, so it is expected that thelong-term application of cooling to the nerves in the posteriorlongitudinal ligament and/or underlying annulus fibrosus may also beundertaken successfully [ROTHMAN S M. The therapeutic potential of focalcooling for neocortical epilepsy. Neurotherapeutics (2, 2009): 251-257].

Furthermore, the reduction of temperature of a nerve by only a fewdegrees, which would not produce significant damage to the nerve, mayalso have a significant effect on the electrophysiology of the nerve[PATBERG W R, Nijmeijer A, Schut J K, Versprille A, Zock J P, Zijlstra WG. Effects of local nerve cooling on conduction in vagal fibres shedlight upon respiratory reflexes in the rabbit. Pflugers Arch 421(2-3,1992):280-282]. Such cooling by may be particularly useful inconjunction with nerve stimulation using one of the energy modalitiesdisclosed here (electrical, mechanical-vibration, light) [ACKERMANN D M,Foldes E L, Bhadra N, Kilgore K L. Nerve conduction block using combinedthermoelectric cooling and high frequency electrical stimulation. JNeurosci Methods. 193(1, 2010): 72-76].

Any type of cooling device could be used in the present application, butthermoelectric (Peltier) coolers are preferred because they have nomoving parts. The thermoelectric cooler has a cold side and a hot side,and two wires per thermoelectric device are used to connected to it to apower source (here, connection to the pulse generator) [BELL L E.Cooling, heating, generating power, and recovering waste heat withthermoelectric systems. Science 321(5895, 2008):1457-1461; CHEN, A. andP. K. Wright. Medical applications of thermoelectrics. Chapter 26, pp.26.1-26.22 In: Thermoelectrics and Its Energy Harvesting (D. M. Rowe,ed). Boca Raton: CRC Press, 2012]. In the present application, the coldside of the thermoelectric cooler is applied to the surface of theposterior longitudinal ligament in the anterior epidural space, and heatis removed from the opposite hot side of the thermoelectric cooler. Thesize of the cooler must be sufficiently small to be mounted in the leaddevice. Examples of the thermoelectric devices that may be used with apercutaneous lead are the 2 mm×1 mm×1.1 mm model MPC-D403/4 fromMicropelt GmbH. Emmy-Noether Strasse 2, 79110 Freiburg, Germany, and the2 mm×1.9 mm×0.6 mm model HV14 thin film thermoelectric module from LairdTechnologies, 3481 Rider Trail South Earth City, Mo. Somewhat largermodels might be used with paddle leads. Examples are the 1.8 mm×3.4mm×3.4 mm model OT08 thermoelectric module from Laird Technologies andthe 5 mm×5 mm×1 mm device that is described by GROSS et al. [A. GROSS,G. Hwang, B. Huang, H. Yang, N. Ghafouri, H. Kim, C. Uher, M. Kaviany,K. Najafi. High-performance micro scale thermoelectric cooler: anoptimized 6-stage cooler. Proceedings of Transducers 2009, Denver,Colo., USA, Jun. 21-25, 2009, pp. 2413-2416].

The heat at the hot side of the device is conducted away to a thermallyconducting layer (e.g., of copper) that lies immediately adjacent to andunder the outer thermal insulator on the side of the lead device nearestthe thecal sac. The heat in that layer is then conducted via a flexiblewire or rod, generally comprising a material that is a good conductor ofheat but a poor conductor of electricity, to the case of the pulsegenerator where the heat will be dispersed and dissipated to surroundingtissue having a relatively large surface area. The wire or rod isthermally insulated on its surface to protect any tissue that it maytouch. Under exceptional circumstances when the devices are producing anunusually large amount of heat, an ice pack may be placed on the surfaceof the skin over an implanted pulse generator. In any case, temperaturein the vicinity of the tissue that is cooled or heated will be monitoredas described previously so as to prevent unintended damage fromoverheating or overcooling.

As described previously in connection with thermal ablation usingelectrodes, the back of the lead device is coated with thermallyinsulating material in order to thermally protect sensitive tissue atall times. In that regard, it is noted that the thermoelectric devicemay itself be used as a heat generator, when mounted on the lead devicewith its hot side towards the posterior longitudinal ligament. Foreither cooling or heating, surface areas (layers) of thermallyconducting material may be mounted or coated onto the side of theelectrically insulating material that is applied to the posteriorlongitudinal ligament, and the thermoelectric device may be applied tothat surface area, instead of to the tissue itself. In that case, thesurface areas may be used to cool the nerve-containing tissue directly,and the thermoelectric device cools the surface areas. The thermallyconducting surface area layer is preferably made of a good thermalconductor that is also a poor electrical conductor, such as diamondpowder, beryllium oxide, hexagonal boron nitride or a polyborazinecompound. For cooling of the tissue, the cold side of the thermoelectricdevice(s) is connected to the surface area, and for heating of thetissue, the hot side of the thermoelectric device(s) is connected to thesurface area. If two or more thermoelectric devices are connected to thethermally conducting surface area, one or more for cooling and one ormore for heating, the user has the option of either cooling or heatingthe tissue that lies adjacent to the surface area(s) of thermallyconducting material, depending on which thermoelectric devices areactivated. Because the lead device will also contain thermometers thatmeasure the temperature of the tissue, a servo circuit may control thethermoelectric devices so as to produce a desired temperature,irrespective of the physiological mechanisms that would otherwisecounteract temperature fluctuations (e.g., variable blood flow andmetabolism). The thermoelectric device itself may be used as thetemperature measuring device using the Seebeck effect. In that case, avoltage is measured that corresponds to the temperature differencebetween the side near the posterior longitudinal ligament and theopposite side of the thermoelectric device, which is thermally connectedto the case of the pulse generator, acting as a body-temperature thermalreservoir. A miniature thermistor, or other thermometer device known inthe art, may also be placed adjacent to the cold or hot side of thethermoelectric device for purposes of temperature measurement, or forverification of the temperature measured by use of the thermoelectricdevice [e.g., PSB-S7 thermistor, Shibaura Electronics USA. 39555 OrchardHill Place, Suite 600, Novi, Mich. 48375].

It is also contemplated that modulation of the temperature of the nervesmay be performed in conjunction with the stimulation of those nerveselectrically, with mechanical vibration, and/or with light. ACKERMANN etal have suggested that it is beneficial to combine cooling andelectrical stimulation, but the combination of cooling with the otherstimulation modalities apparently has not been disclosed previously[ACKERMANN D M, Foldes E L, Bhadra N, Kilgore K L. Nerve conductionblock using combined thermoelectric cooling and high frequencyelectrical stimulation. J Neurosci Methods 193(1, 2010):72-76].

In order to characterize the pathophysiology of the patient's lumbarpain and use that characterization to select energy modalities andparameters of therapeutic stimulation, in one embodiment of theinvention the electrodes of the implanted lead device are first used asrecording or measurement electrodes, rather than as stimulationelectrodes. Thus, when the implanted electrodes are in contact with theposterior longitudinal ligament and/or annulus fibrosus, voltages aremeasured from each implanted electrode. The voltages are referencedrelative to the voltage at any suitable location. For example, the metalcasing of the pulse generator may be used as the ground reference point,or any of the electrodes may be selected to be a voltage reference.

If the electrodes are constructed as closely spaced concentric rings (orsquares, etc.) of conducting material around a conducting central disc,separated by a narrow bands of electrical insulation, the surface areaof the electrode may be selected by electrically connecting one or moreof the concentric rings to the central disc via their separateconnecting wires, thereby forming a compound electrode. One may alsotreat an outer ring of the electrode assembly as a ground and measureelectrical potentials of the inner electrode components relative to theouter electrode ring. Thus, the surface area of the electrode at anyparticular location on the lead device need not be predetermined, andthe surface area of an electrode even need not be the same when used forelectrical stimulation, rather than for recording or measurement.

The voltages measured at each of the (generally compound) electrodes atdifferent locations on the lead device are expected to fluctuatespontaneously. Some of that fluctuation may reflect electronic noise,but much of the fluctuation may be attributed to physiological voltagefluctuations at the site underlying the electrode in the posteriorlongitudinal ligament and/or annulus fibrosus. The voltage fluctuationsmay be regarded as local field potentials, the mechanistic origins ofwhich may be analyzed in terms of current source densities [BEDARD C,Kroger H, Destexhe A. Modeling extracellular field potentials and thefrequency-filtering properties of extracellular space. Biophys J 86(3,2004):1829-1842].

If the measured voltages are filtered to remove frequencies lower than500 Hz, spike trains might be visible at those higher frequencies,originating from an unknown number of spiking neurons in the immediatevicinity of the electrode. Characterization and analysis of such a spiketrain, if observed, may be performed by interpreting it as a pointprocess [BROWN E N, Kass R E, Mitra P P. Multiple neural spike traindata analysis: state-of-the-art and future challenges. Nat Neurosci 7(5,2004):456-461].

When the Fourier spectrum of the measured voltages at each of theelectrodes is calculated, peaks may be observed in the spectrum. Suchpeaks may be attributed to voltage oscillations, and the peak narrownesscharacterizes the regularity of the oscillation. Some of the observedneural activity fluctuations may be due to intrinsic spontaneousactivity of the nerves, but other activity may be attributed to thefunction of the nerves in a larger neural network. Because nerves of thetissue under the electrodes may be comprised in part of sympatheticnerves of the autonomic nervous system, some peaks so measured mayreflect oscillations in the activity of the sympathetic nervous systemas a whole, involving arterial baro-receptors, respiration, brainstemoscillators involved in thermoregulation and peripheral blood flow, andthe like. Other oscillations may be related to central patterngenerators of the spinal cord involving repetitive movements, such aslocomotion or sexual activity, that may persist to some extent even inthe absence of such activity, somewhat analogous to the persistence ofoscillations in resting state networks in the brain [Simon M DANNER,Frank Rattay, Ursula S Hofstoetter, Milan R Dimitrijevic, KarenMinassian. Locomotor rhythm and pattern generating networks of the humanlumbar spinal cord: an electrophysiological and computer modeling study.BMC Neuroscience 14(Suppl 1, 2013):P274, pp 1-2]. Other fluctuations inthe voltages may be attributed to fluctuating movement of the lumbarspine and its effect on mechanoreceptors, to whether the patient isawake or asleep, to whether the patient's bladder is filling, etc.

Power in the spectrum of fluctuations may be filtered into frequencybands, analogous to the frequency bands of an EEG (delta<4 Hz, theta 4-8Hz, alpha 8-13 Hz, beta 13-21 Hz, sensorimotor 12-15 Hz, high beta 20-32Hz, and gamma 32+Hz), but selection of the endpoints of the bands in thepresent application would be based primarily on their usefulness inanalyzing their contribution to the patient's pain (see below). Over awide range of frequencies, the fluctuations are expect to have 1/fscaling with a slope that varies from patient to patient when plottedagainst the logarithm of frequency, and that slope may be used tocharacterize the electrophysiology of the nerves in the posteriorlongitudinal ligament and underlying annulus fibrosus [LIU X,Eschenfelder S, Blenk K H, Jänig W, Flabler H. Spontaneous activity ofaxotomized afferent neurons after L5 spinal nerve injury in rats. Pain84(2-3, 2000):309-318; SEKINE, M; Yamashita, T; Sakamoto, N;Takebayashi, T; Ishii, S. Mechanosensitive afferent units in the lumbarposterior longitudinal ligament. Poster Session. 47th Annual Meeting,Orthopaedic Research Society, Feb. 25-28, 2001, San Francisco, Calif.;SEKINE M, Yamashita T, Takebayashi T, Sakamoto N, Minaki Y, Ishii S.Mechanosensitive afferent units in the lumbar posterior longitudinalligament. Spine (Phila Pa. 1976) 26(14, 2001):1516-1521; MIKI K, Oda M,Kamijyo N, Kawahara K, Yoshimoto M. Lumbar sympathetic nerve activityand hindquarter blood flow during REM sleep in rats. J Physiol 557(Pt 1,2004):261-271].

It is understood that the voltage time-series at the several electrodeswill generally not be independent of one another, so that Fourieranalysis in two (or more) dimensions should be undertaken in order tocharacterize the covariance of the different electrodes' voltages. It isalso understood that wavelet and other types of transforms of the dataor other types of analysis may be performed in addition to, or insteadof, the Fourier analysis [RODRIGUEZ E E, Hernández-Lennus E, Itzá-OrtizB A, Jiménez I, Rudomín P. Multichannel detrended fluctuation analysisreveals synchronized patterns of spontaneous spinal activity inanesthetized cats. PLoS One 6(10, 2011):e26449, pp. 1-11; D.Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U, and Choo MinLim. EEG signal analysis: A survey. J Med Syst 34(2010):195-212). It isalso understood that measurement of voltages with one or more electrodesmay be useful for the placement of the lead device. For example, ifvoltages are initially measured with the lead at more than one position,one may then devise and configure the ultimate location of thestimulation energy that would optimally reduce the patient's pain. Inparticular, one may devise and configure the ultimate location of thestimulation so as to correspond to electrode sites that exhibitsignificant spontaneous voltage fluctuations originating in oscillationsin the sympathetic nervous system, as confirmed, e.g., by heart ratevariability analysis. The recording of local field potentials hasheretofore been used as a guide to the selection of which electrodesamong an array are to be used for stimulation, but only in connectionwith deep brain stimulation in which minute changes in electrodeposition may correspond to very large differences in neural function[U.S. Pat. No. 8,670,830, entitled Stimulation electrode selection, toCARLSON et al.; U.S. Pat. No. 8,078,281, Apparatus for treatingneurological disorders by means of chronic adaptive brain stimulation asa function of local biopotentials, to PRIORI et al]. In contrast, thepresent invention is concerned with measurement of nerve activity inperipheral nerves that are related to the generation of pain, for whichthe very existence of local field potentials appears to be a noveldisclosure.

The measurement of voltage time-series as described above characterizesthe electrophysiology of nerves in the posterior longitudinal ligamentand underlying annulus fibrosus only at sites directly under theelectrodes. The invention contemplates an additional form of measurementusing the electrodes that may also be used to characterize theelectrophysiology of the tissue between the electrodes. That additionalform of measurement makes use of electrical impedance tomography (EIT),which produces a map of electrical conductivity in the region bounded bythe measurement electrodes. In addition to the electrodes of the lead,surface EIT electrodes may also be placed on the patient's skin anteriorto the disc. Small alternating currents are applied sequentially toelectrodes, and the resulting equi-potentials are recorded from theother electrodes. This process is repeated for different electrodeconfigurations, and finally an essentially two-dimensional surfacetomogram is constructed using an algorithm that solves the correspondinginverse problem [BROWN B H. Electrical impedance tomography (EIT): areview. J Med Eng Technol 27(3, 2003):97-108; DAVALOS R V, Otten D M,Mir L M, Rubinsky B. Electrical impedance tomography for imaging tissueelectroporation. IEEE Trans Biomed Eng 51(5, 2004):761-767; LINDERHOLMP, Marescot L, Loke M H, Renaud P. Cell culture imaging usingmicroimpedance tomography. IEEE Trans Biomed Eng 55(1, 2008):138-146;BOYLE, A., Adler, A. Lionheart, W. R. B. Shape deformation intwo-dimensional electrical impedance tomography. IEEE Transactions onMedical Imaging 31(12, 2012): 2185-2193].

Because the relaxed lumbar spine is curved, the patient shouldpreferably bend forward (flex) by different angles while performing theEIT, in order that the posterior longitudinal ligament and/or underlyingannulus fibrosus lie within the region bounded by the device'selectrodes (i.e., flex beyond lumbar lordosis into kyphosis) [CONSMULLERT, Rohlmann A, Weinland D, Druschel C, Duda G N, Taylor W R. Comparativeevaluation of a novel measurement tool to assess lumbar spine postureand range of motion. Eur Spine J 21(11, 2012):2170-2180; CONSMULLER T,Rohlmann A, Weinland D, Druschel C, Duda G N, Taylor W R. Velocity oflordosis angle during spinal flexion and extension. PLoS One 7(11,2012):e50135, pp. 1-7]. Variation of the lumbar flexure angle(preferably with limited hip flexure) in small steps allows foressentially two-dimensional image surfaces at each angle to be builtinto a three-dimensional EIT image that compensates for theangle-dependent lumbar strains and conductivity changes. Thus, use ofEIT may produce a tomographic image of the tissue volume nearest theelectrodes, containing the ligament and annulus. In general, the annulusshould be distinguishable from the ligament in such an EIT image becausethe annulus is reported to have an electrical conductivity that is morethan twice that reported for ligaments [JUSTIZ, A M, Cheung, H and Gu, WY. Electrical conductivity of annulus fibrosus. Poster Session—47thAnnual Meeting, Orthopaedic Research Society, Feb. 25-28, 2001, SanFrancisco, Calif.; GU W Y, Justiz M A, Yao H. Electrical conductivity oflumbar annulus fibrosis: effects of porosity and fixed charge density.Spine 27(21, 2002):2390-2395; Anonymous. Tendon/Ligament. ElectricalConductivity Tissue Frequency Chart. Tissue Properties Database. IT'ISFoundation. ETH Zentrum, E T Z. C H-8092 Zurich. Switzerland]. Tearswithin the annulus should also be distinguishable from the remainder ofthe annulus, because the tears contain zones of vascularized granulationmaterial that would have a different conductivity than the remainder ofthe annulus [PENG B, Wu W, Hou S, Li P, Zhang C, Yang Y. Thepathogenesis of discogenic low back pain. J Bone Joint Surg Br 87(1,2005): 62-67]. Consequently, the 3-dimensional EIT image will containmuch of the information that is currently provided by discography andcan either complement the discography or substitute for it. Once thelead is implanted within the anterior epidural space, such EIT imagingmay be performed repeatedly, in order to track changes in the PLL andannulus fibrosus over time. Sequential EIT imaging would also be usefulwhen electroporation is being used to damage nerves, as described above,because the EIT imaging would document accompanying changes inconductivity in tissue in the vicinity of the nerves that were beingelectroporated [DAVALOS R V, Otten D M, Mir L M, Rubinsky B. Electricalimpedance tomography for imaging tissue electroporation. IEEE TransBiomed Eng 51(5, 2004):761-767; GRANOT Y, Rubinsky B. Methods ofoptimization of electrical impedance tomography for imaging tissueelectroporation. Physiol Meas 28 (10, 2007):1135-1147; LINDERHOLM P,Marescot L, Loke M H, Renaud P. Cell culture imaging usingmicroimpedance tomography. IEEE Trans Biomed Eng 55(1, 2008):138-146].

The EIT is preferably performed by applying very low alternating currentof different frequencies to the different electrodes, in order that theconductivity imaging be performed in real time [Yair GRANOT and BorisRubinsky. Methods of optimization of electrical impedance tomography forimaging tissue electroporation. Physiol. Meas. 28(2007):1135-1147]. Overshort time periods (e.g., about 1 second), the conductivity tomographicimages may be averaged so as to reduce noise. But over longer timeperiods, the images may be observed to fluctuate due, for example, tofluctuations in the fluid and electrolyte content of the imaged region.Accordingly, the same type of fluctuation analysis that was describedabove for the time-varying voltages at the individual electrodes may beperformed for small regions throughout the imaged region. It isunderstood that the above-mentioned voltage time-series measured at theseveral electrodes will generally not be independent of the EIT data, sothat Fourier analysis in two (or more) dimensions should be undertakenin order to characterize the covariance of the two types of data[JACKSON A R, Travascio F, Gu W Y. Effect of mechanical loading onelectrical conductivity in human intervertebral disk. J Biomech Eng131(5, 2009):054505: pp. 1-15; TRAVISCIO F, Jackson A R, Brown M D, Gu WY. Relationship between solute transport properties and tissuemorphology in human annulus fibrosus. J Orthop Res 27(12,2009):1625-1630].

Furthermore, because the EIT image characterizes the conductivity of thetissue, it may be used in other ways to select the parameters of nervestimulation. In particular, the EIT data may be used to devise andconfigure the voltages on the electrodes in such a way as topreferentially stimulate selected parts of the posterior longitudinalligament and/or the underlying annulus fibrosus. In order to motivate amethod for preferentially stimulating a particular volume of theposterior longitudinal ligament and/or annulus fibrosus by reversibleelectrical stimulation, it is useful to first summarize the relevantphysics of electric fields and currents that are produced by theelectrodes. Ampere's law with Maxwell's correction may be written as:∇·J+∇·ε(∂E/∂t)=0, where J is the electrical current density, E is theelectric field, ε is the permittivity, and t is time. Under theassumption that changes in the magnetic field may be ignored, E may bewritten as the gradient of a scalar potential Φ:E=−∇Φ. The electricalcurrent density J is determined by the electric field and conductivityas follows, where the conductivity σ is a function of position:J=σE=−σ∇Φ. If the current flows in material that is essentiallyunpolarizable (i.e., is presumed not to be a dielectric so that ε=0) orif a time-independent (steady state) solution is desired, substitutionof the expression for J into the above expression for Ampere's law gives−∇·(σ∇Φ)=0, which is a form of Laplace's equation [Richard P. FEYNMAN,Robert B. Leighton, and Matthew Sands. The Feynman Lectures on Physics.Volume II. Addison-Wesley Publ. Co. (Reading M A, 1964), page 15-15].Thus, given the positions and sizes of the electrodes that are part ofthe lead device, given the conductivity as a function of position withinthe tissue that was measured using EIT, and given the voltages that areapplied to the electrodes, then the three-dimensional distribution ofthe electrical potential and electric field within the posteriorlongitudinal ligament or annulus fibrosus may be estimated by solvingthe corresponding Laplace's equation. The more general equations mayalso be evaluated in order to take into account time-dependent effects,particularly the effect of pulse width on distance from the electrodes[SZLAVIK R B, de Bruin H. The effect of stimulus current pulse width onnerve fiber size recruitment patterns. Med Eng Phys 21(6-7,1999):507-515].

In the present invention, this model of the electric field within theposterior longitudinal ligament and annulus fibrosus is exercised byvarying possible voltages supplied to the electrodes of the lead, inorder to find the combination of electrode voltage amplitudes thatmaximize stimulation of the tissue in the region of interest (e.g.,maximize the electric field amplitude) and minimize stimulation in otherregions. Laplace's equation has been solved numerically in order tocompare different electrode shapes and numbers for transcranialstimulation, but its use in connection with an implanted lead isapparently new. Furthermore, its use is new here because it makes use ofthe conductivities that had been measured by EIT [Abhishek DATTA, MagedElwassif, Fortunato Battaglia and Marom Bikson. Transcranial currentstimulation focality using disc and ring electrode configurations: FEManalysis. J. Neural Eng. 5 (2008): 163-174].

When the electrodes of the lead are being used for recording andmeasurement, as described above, the invention contemplates thesimultaneous measurement of the patient's pain, so as to correlate thevoltage fluctuations with the pain. The pain measurement may be based onself-reporting of the patient, typically in a numeric range of 0-10 with0 as no pain, 1-3 as mild pain, 4-6 as moderate pain, and 7-10 as severepain. Alternatively, there may be an objective measurement of paininvolving psychometric evaluation of the patient, by an observer viewingsuch behaviors as facial grimacing, groaning, or writhing [LI D,Puntillo K, Miaskowski C. A review of objective pain measures for usewith critical care adult patients unable to self-report. J Pain 9(2008):2-10; LABUS J S, Keefe F J, Jensen M P. Self-reports of pain intensityand direct observations of pain behavior: when are they correlated? Pain102(1-2, 2003):109-124]. Physiological measurements may also be used toestimate the level of pain without the need for an observer, includingthe measurement of features within an EEG and measurement of one or moreautonomic physiological variables (heart rate variability, electrodermalactivity, as described below) [TOUSIGNANT-Laflamme Y, Rainville P,Marchand S. Establishing a link between heart rate and pain in healthysubjects: a gender effect. J Pain 6(2005): 341-347; HAMUNEN K, KontinenV, Hakala E, Talke P, Paloheimo M, Kalso E. Effect of pain on autonomicnervous system indices derived from photoplethysmography in healthyvolunteers. Br J Anaesth 108(5, 2012):838-844; NIR R R, Sinai A, Raz E,Sprecher E, Yarnitsky D. Pain assessment by continuous EEG: associationbetween subjective perception of tonic pain and peak frequency of alphaoscillations during stimulation and at rest. Brain Res 1344(2010):77-86]. In preferred embodiments, the EEG sensors may compriseambulatory sensors [CASSON A, Yates D, Smith S, Duncan J,Rodriguez-Villegas E. Wearable electroencephalography. What is it, whyis it needed, and what does it entail? IEEE Eng Med Biol Mag. 29(3,2010):44-56; NIKULIN V V, Kegeles J, Curio G. Miniaturizedelectroencephalographic scalp electrode for optimal wearing comfort.Clin Neurophysiol 121(7, 2010):1007-1014]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34(2010):195-212].

It is understood that for certain scalp electrode recordings, such asthe recording of a P300 event-related potential, the measurement mayindicate the patient's conscious recognition of a painful event, ratherthan subconscious neural processing of the painful stimuli [ZASLANSKY R,Sprecher E, Katz Y, Rozenberg B, Hemli J A, Yarnitsky D. Pain-evokedpotentials: what do they really measure? Electroencephalogr ClinNeurophysiol 100(5, 1996):384-391; GROSS J, Schnitzler A, Timmermann L,Ploner M. Gamma oscillations in human primary somatosensory cortexreflect pain perception. PLoS Biol 5(5, 2007):e133:1168-1173]. However,it is also possible to assess the degree of pain even in unconsciousindividuals, by using fMRI to image particular regions of the patient'sbrain that receive signals about painful stimuli [Tor D. WAGER, LaurenY. Atlas, Martin A. Lindquist, Mathieu Roy, Choong-Wan Woo and EthanKross. An fMRI-Based Neurologic Signature of Physical Pain. N Engl J Med368(2013):1388-1397; Dieter VAITL. Interoception. Biological Psychology42 (1996):1-27; CRITCHLEY H D, Wiens S, Rotshtein P, Ohman A, Dolan R J.Neural systems supporting interoceptive awareness. Nat Neurosci 7(2,2004):189-195; CRAIG, A. D. How do you feel? Introception: the sense ofthe physiological condition of the body. Nat. Rev. Neurosci3(2002):655-666; CRAIG A D. How do you feel—now? The anterior insula andhuman awareness. Nat Rev Neurosci 10(1, 2009):59-70].

Several non-invasive measurements can be used to assess sympatheticactivity in a patient, and they may provide an indication ofparasympathetic activity as well [MENDES, W. B. Assessing the autonomicnervous system. Chapter 7 In: E. Harmon-Jones and J. Beer (Eds.) Methodsin Social Neuroscience. New York: Guilford Press, 2009, pp. 118-147].One such method involves extracting variability of the heart rate from ameasurement of the patient's electrocardiogram (ECG). The ECG sensorsmay be embedded in garments or placed in sports wristwatches, ascurrently used in programs that monitor the physiological status ofsoldiers [G. A. SHAW, A. M. Siegel, G. Zogbi, and T. P. Opar. Warfighterphysiological and environmental monitoring: a study for the U.S. ArmyResearch Institute in Environmental Medicine and the Soldier SystemsCenter. MIT Lincoln Laboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141].Those ECG sensors should be adapted to the automatic extraction andanalysis of particular features of the ECG, including indices of P-wavemorphology, as well as heart rate variability indices of parasympatheticand sympathetic tone. Heart rate variability is conventionally assessedby examining the Fourier spectrum of successive heart rate intervalsthat are extracted from an electrocardiogram (RR-intervals). However,more elaborate indices of sympathetic and parasympathetic activity mayalso be extracted from the variation in successive heart rate intervals.Additional noninvasive measures of sympathetic activity, such asvariability of QT intervals, are preferably measured as well. A signalrepresenting respiration may also be derived from the ECG, orrespiration may be independently measured noninvasively using methodsknown in the art, such as using a nose thermistor, inductiveplethysmography, mercury in silastic strain gauges, impedancepneumography, and noninvasive respiratory volume monitoring [U. RajendraACHARYA, K. Paul Joseph, N. Kannathal, Choo Min Lim and Jasjit S. Suri.Heart rate variability: a review. Medical and Biological Engineering andComputing 44(12, 2006), 1031-1051; BOETTGER S, Puta C, Yeragani V K,Donath L, Müller H J, Gabriel H H, Bär K J. Heart rate variability, QTvariability, and electrodermal activity during exercise. Med Sci SportsExerc 42(3, 2010):443-448; Sung-Bin PARK, Yeon-Sik Noh, Sung-Jun Park,Hyoung-Ro Yoon. An improved algorithm for respiration signal extractionfrom electrocardiogram measured by conductive textile electrodes usinginstantaneous frequency estimation. Med Bio Eng Comput46(2008):147-158].

Electrodermal measurements, also known as galvanic skin responses, havebeen used traditionally in psychophysiology to indicate the patient'semotional and/or cognitive state and sympathetic tone. Ordinarily, suchmeasurement is made on the palm, volar side of a finger, or feet of apatient, although electrodermal measurement at other sites such as theshoulder may be useful as well. In the present application the preferredsite is below the lumbar spine, such as the soles of the feet [Mariekevan DOOREN, J. J. G. (Gert-Jan) de Vries, Joris H. Janssen. Emotionalsweating across the body: Comparing 16 different skin conductancemeasurement locations. Physiology & Behavior 106(2012): 298-304]. Since1981, a particular skin conductance method has been the internationalstandard technique to record and analyze electrodermal activity (EDA)[Wolfram BOUCSEIN. Electrodermal activity, 2nd Ed., New York: Springer,2012, pp. 1-618]. Both short-term electrodermal responses to stimuli andlonger term spontaneous electrodermal activity levels are measured.Recently, miniature electrodermal sensors have become available for usein ambulatory monitoring [Ming-Zher P O H, Nicholas C. Swenson, andRosalind W. Picard. A wearable sensor for unobtrusive, long-termassessment of electrodermal activity. IEEE Transactions on BiomedicalEngieering 57(5, 2010):1243-1252; Ming-Zher P O H, Tobias Loddenkemper,Nicholas C. Swenson, Shubhi Goyal, Joseph R. Madsen and Rosalind W.Picard. Continuous monitoring of electrodermal activity during epilepticseizures using a wearable sensor. 32nd Annual International Conferenceof the IEEE EMBS, Buenos Aires, Argentina, Aug. 31-Sep. 4, 2010, pp.4415-4418; Ming-Zher P O H, Tobias Loddenkemper, Claus Reinsberger,Nicholas C. Swenson, Shubhi Goyal, Mangwe C. Sabtala, Joseph R. Madsen,and Rosalind W. Picard. Convulsive seizure detection using a wrist-wornelectrodermal activity and accelerometry biosensor. Epilepsia 53(5,2012):e93-e97].

In normal individuals, norepinephrine released from sympathetic nervesonto alpha receptors in blood vessels causes vasoconstriction. Thus, anincrease or decrease in sympathetic tone would normally result in adecrease or increase in blood flow to the lumbar region, respectively.Consequently, the measurement of changes in blood flow may be used toinfer changes in the sympathetic activity that caused the blood flowchanges, whether the changes occur spontaneously or in response tostimulation. The situation is more complex in tissue that isexperiencing inflammation. Initially, the vasoconstrictive capacity ofsympathetic nerve fibers is counteracted by a hyperemic response thatpromotes vasodilation due to the release of vasoactive mediators(histamine, bradykinin, neuropeptides, prostaglandins) that are producedby mast cells, macrophages, fibroblasts, parenchymal cells, the vesselwall, and possibly the sympathetic nerves themselves. But eventually, itis expected that the long-term steady-state response to inflammationwould be a reduction in tissue blood flow, rather than that temporaryhyperemia. One general explanation for this variable blood flow is thatthe receptor composition of the lumbar blood vessels and nerves changesthroughout the inflammatory process [GRANGER D N, Senchenkova E.Inflammation and the Microcirculation. Chapter 4. pp. 15-18 in: SanRafael (Calif.): Morgan & Claypool Life Sciences, 2010; ESPAHBODI S,Doré C J, Humphries K N, Hughes S P. Color Doppler ultrasonography oflumbar artery blood flow in patients with low back pain. Spine (PhilaPa. 1976) 38(4, 2013):E230-E236].

Therefore, the present invention also discloses methods to evaluate therelation or correlation between regional sympathetic tone and the localflow of blood within the lumbar region. The measurement of fluctuationsin regional sympathetic tone was described above, e.g., the measurementof fluctuations in the patient's electrodermal activity on one or bothfeet. The measurement of local blood flow in the present invention makesadditional use of the optical fibers and lasers that were describedabove in connection with the stimulation of the nerves with light. Inaddition to that usage, laser Doppler flowmetry can be performed usingthose same optical fibers and laser diodes, resulting in a measurementof the flow of blood in the tissue that is illuminated with the laser.The laser Doppler flowmetry may be performed with each of many singleoptical fibers that are directed to different areas of the posteriorlongitudinal ligament and/or annulus fibrosus (see FIG. 8) [U.S. Pat.No. 4,590,948, entitled Method and apparatus for measuring the bloodflow in the superficial blood vessels of tissue, to NILSSON; CAI H,Pettersson H, Rohman H, Larsson S E, Oberg P A. A new single-fibre laserDoppler flowmeter based on digital signal processing. Med Eng Phys 18(7,1996):523-528; H. CAI, H. Rohman, S. E. Larsson, P. Å. Öberg. LaserDoppler flowmetry: characteristics of a modified single-fibre technique.Medical and Biological Engineering and Computing 34(1, 1996):2-8;Shimpei KOHRI, Tsutomu Tajikawa, Kenkichi Ohba. Development of aminiaturized fiber-optic LDV sensor for local blood velocitymeasurement. Biomedical Engineering Research 2(3, 2013):131-138].Alternatively, miniature Doppler flowmeters may be mounted into the leaddevice itself, without using optical fibers [Yoshinori KIMURA, MasakiGonna, Atsushi Onoe, Eiji Higurashi, and Renshi Sawada. Integrated laserDoppler blood flowmeter designed to enable wafer-level packaging. IEEETransactions on Biomedical Engineering 57(8, 2010): 2026-2033].

Thus, in preferred embodiments, measurement of the patient's pain willbe by self-reporting (e.g., pushing one of several event-marker buttonsto record the pain level, used in conjunction with laser Dopplermeasurement of blood flow and non-invasive measurement of the patient'sEEG and autonomic tone (heart rate variability, electrodermal activity).For situations in which self-reporting is not practical (e.g., when thepatient has dementia, when the patient is in some state of anesthesis orduring veterinary procedures), the EEG and autonomic tone measurementsmay be supplemented with psychometric evaluation of pain and/or theevaluation of pain levels using fMRI.

The activity of nerves within the posterior longitudinal ligament and inthe underlying annulus fibrosus is expected to depend in part on themechanical stresses and strains in those anatomical locations,particularly because afferent nerve fibers in those locations are mainlymechanosensitive nociceptive fibers, classified into Group III and GroupIV types, with a high mechanical threshold for activation [SEKINE M,Yamashita T, Takebayashi T, Sakamoto N, Minaki Y, Ishii S.Mechanosensitive afferent units in the lumbar posterior longitudinalligament. Spine26(14, 2001): 1516-1521]. The stresses and strains atthose locations in turn depend on the movements and postures in thelumbar region of the spine, which may be made provocatively and underdifferent loads (e.g., lifting a weight) as flexions (bending forward)and extensions (bending backwards); lateral bending (left, right); andaxial rotation (clockwise, counterclockwise). If the patient isambulatory, he or she will undergo combinations of these movementsthroughout the day, which may be associated with activities such assitting or standing with different postures, the lifting of objects, andphysical activity in general [ADAMS M A. Biomechanics of back pain.Acupunct Med 22(4, 2004):178-188; ADAMS M A, Dolan P. Spinebiomechanics. J Biomech 38(10, 2005):1972-1983; Robert J. KOWALSKI, LisaA. Ferrara, and Edward C. Benzel. Biomechanics of the Spine. Neurosurg Q15(1, 2005): 42-59]. Thus, the invention also contemplates long-term(e.g., 24 hour) ambulatory measurement of the spontaneous electricalfluctuations that may be measured from the electrodes, along with thesimultaneous measurement of the patient's pain and the measurement ofvariables that may be used to predict those data (e.g., stresses andstrains in the lumbar region of the spine).

Alteration in the stresses and strains in the anterior annulus fibrosusand posterior longitudinal ligament may also be made provocativelyduring the course of the performance of discography. In fact,discography and implantation of the devices disclosed here may becombined into a single procedure, during which time stresses and strainsare measured [LEE S H, Derby R, Chen Y, Seo K S, Kim M J. In vitromeasurement of pressure in intervertebral discs and annulus fibrosuswith and without annular tears during discography. Spine J 4(6,2004):614-618; SEO K S, Derby R, Date E S, Lee S H, Kim B J, Lee C H. Invitro measurement of pressure differences using manometry at variousinjection speeds during discography. Spine J. 7(1, 2007):68-73].

The movements of the lumbar spine may be measured continuously byembedding preferably two or more miniature accelerometers and/orgyroscopes into the implanted lead device, e.g., at its ends. Forexample, the accelerometers may be the 2 mm×2 mm×0.98 mm Bosch ModelBMA220 (Bosch Sensortec, 1800 W. Central Road Mount Prospect, Ill.60056). Integration of the acceleration data provides velocity andposition data, so those data characterize much of the patient'sactivity, and they may be used to infer deformations of the disc andligaments [PEARCY M J, Tibrewal S B. Lumbar intervertebral disc andligament deformations measured in vivo. Clin Orthop Relat Res (191,1984):281-286].

The stresses within the implanted device and at the interface betweenthe device and the posterior longitudinal ligament and/or annulus may bemeasured with miniature stress sensors embedded into the lead device,with the stress sensors placed in the vicinity of the one or moreselected tissue locations [ADAMS M A, McNally D S, Dolan P. “Stress”distributions inside intervertebral discs. J Bone J Surg78(1996):965-972]. Although the stress sensor could be like the onedescribed by GLOS et al. for measuring compression within the annulus, apreferred stress sensor is of the type described by ALFARO, not onlybecause of its 3 mm×3 mm×0.3 mm size, but also because it can measureshear stress at the device/tissue boundary in addition to normalstresses [GLOS D L, Sauser F E, Papautsky I, Bylski-Austrow D I.Implantable MEMS compressive stress sensors: Design, fabrication andcalibration with application to the disc annulus. J Biomech 43(11,2010):2244-2248; Fernando ALFARO, Lee Weiss, Phil Campbell, Mark Millerand Gary K Fedder. Design of a multi-axis implantable MEMS sensor forintraosseous bone stress monitoring J. Micromech. Microeng.19(2009):085016, pp. 1-13].

It is possible in principle to model and analyze the measured stressesand strains using finite element analysis, as a function of bodymovements in the vicinity of the posterior longitudinal ligament andposterior annulus fibrosus [LI H, Wang Z. Intervertebral discbiomechanical analysis using the finite element modeling based onmedical images. Comput Med Imaging Graph 30(6-7, 2006):363-370; DOLAN P,Adams M A. Recent advances in lumbar spinal mechanics and theirsignificance for modelling. Clin Biomech (Bristol, Avon) 16 (Suppl 1,2001):58-516]. However, this is difficult in practice because vertebralcomponents are viscoelastic, such that stresses are functions not onlyof current anatomical positions, but also of velocities and histories[ADAMS M A, Dolan P. Time-dependent changes in the lumbar spine'sresistance to bending. Clin Biomech 11(4, 1996):194-200]. They may evendepend on the time of day. Compounding the difficulty of modeling lumbarstresses and strains is the contribution of back muscles that contractand relax reflexively in response to shifting loads [Z. LADIN and K. M.Neff. Testing of a Biomechanical Model of the Lumbar Muscle ForceDistribution Using Quasi-Static Loading Exercises. J Biomech Eng 114(4,1992), 442-449; PANJABI M M. Clinical spinal instability and low backpain. J Electromyogr Kinesiol 13(4, 2003):371-379; PANJABI M M. Ahypothesis of chronic back pain: ligament subfailure injuries lead tomuscle control dysfunction. Eur Spine J 15(5, 2006):668-676; ROLAND M OA critical review of the evidence for a pain-spasm-pain cycle in spinaldisorders. Clin Biomech (Bristol, Avon) 1(1986):102-109].

Therefore, when the above-mentioned accelerometer and stress-sensormeasurements are being made in order to characterize the time-varyingbiomechanics of the lumbar spine in the vicinity of the implanteddevice, a more complete characterization may be made by usingsimultaneous back-surface electromyography (EMG) to measure activity ofthe nearby erector spinae muscle group (longissimusm, iliocostalis, andspinalis muscles). Such measurements would be particularly useful whenperforming simultaneous ambulatory monitoring of the patient's pain,nerve activity, and biomechanics [CASSISI J E, Sexton-Radek K,Castrogiovanni M, Chastain D, Robinson M E. The use of ambulatory EMGmonitoring to measure compliance with lumbar strengthening exercise.Biofeedback Self Regul 18(1, 1993):45-52; DOLAN P, Earley M, Adams M A.Bending and compressive stresses acting on the lumbar spine duringlifting activities. J Biomech 27(10, 1994):1237-1248].

The structure of lead devices containing the above-mentioned componentsis illustrated in the examples shown in FIG. 8. The lead shown in FIG.8A is intended to be placed horizontally within the anterior epiduralspace, across one of the patient's discs and across nerves withinintervertebral fibers of the posterior longitudinal ligament. The leadshown in FIG. 8B is intended to be placed vertically (longitudinally) tostimulate nerves in vertebral fibers of the posterior longitudinalligament, as well as portions of two (or more) of the patient's discsand intervertebral fibers of the PLL. All stimulating electrodes 61 ofthe lead devices (and devices involving other forms of energy) areunidirectional, such that the electrode contacts are located on one sideof the electrically insulating substrate of the lead device 62 that ismade of a flexible material. On the side that is to face the posteriorlongitudinal ligament (the electrode side), the electrically insulatingsubstrate is made with, or coated with, a thermally conducting materialthat is also an electrical insulator. On the opposite side that wouldface the thecal sac, the lead device is coated with a thermal insulatorsuch as ceramic foam. The electrode contacts in FIG. 8A are visible inthe view 95. When that view is rotated by 90 degrees, as in the viewlabeled as 96, a cross section of that rotated view would reveal theelectrodes 61, wires 63 that connect the electrode to a pulse generator64, and channels 97 through which those wires run. In view 96, theelectrode-side of the electrical insulator substrate 62 is shown to becoated with the material that is a good thermal conductor but that isalso a good electrical insulator. On the opposite side of the lead,there is a layer of material that is a good thermal conductor 115, andon the very outside surface of the lead there is a layer of materialthat is a good thermal insulator 116. The layer 115 is used to conductheat that is generated within the lead to the case of the pulsegenerator, and the thermal insulator 116 protects the thecal sac andnerve roots from any heat produced by the lead. When the view 95 isrotated by 180 degrees to produce the view labeled as 98, the electrodesand other surface-mounted components are no longer visible. Thus, onlythe insulating material may be seen from that back side (underlyingelectrode locations are indicated with dotted lines, and the locationsof other components are shown, but they would not be visible in view98). Radio-opaque directional indicators 65 are also shown to be locatedwithin the leads. The lead device also contains small tabs 99 that areused to anchor the lead to bone or other relatively immobile tissue.

The lead devices shown in FIG. 8 contain additional components that weredescribed above. In the figure, symbols are used to indicate theapproximate location and size of the following components: electrode 61,optical fiber 120 carrying light to illuminate the tissue, vibrator 130,thermoelectric cooler 140, which is also used as a thermometer and couldalso be used as a heater if reversed, accelerometer 150 for monitoringposition, and stress sensor 160. The connections going from the leaddevice to the pulse generator 64 can be situated at the end of the leaddevice 108 or on the side of the device 109, or both. As shown in FIG.8B, a bundle of wires 109 connect the lead's components to correspondingcircuits within the pulse generator 64. The circuits include those forelectrical pulse generation for voltages V₁, V₂, . . . V_(N) atelectrodes 1, 2, . . . N, electrical measurements involving theelectrodes when the electrodes are switched from pulse generation tomeasurement mode, vibration pulse generation, cooling pulses involvingthe thermoelectric devices, temperature measurement, measurement ofposition and velocity with the accelerometers, and measurement ofmechanical stresses. As also shown in FIG. 8B, a bundle of opticalfibers 108 carries light from two laser diodes (e.g., ultraviolet andinfrared) to the sites on the lead device where tissue is stimulatedoptically. The pulses of light are produced by the light pulse generatorshown in the figure. The light pulse generator may also be used in alaser Doppler flowmeter mode, ordinarily with an infrared laser, inorder to measure blood flow. A wire is also shown in that figure toconnect the lead device thermally via thermally conducting material 115to the case of the pulse generator 64. The thermally conducting casethen serves as a heat reservoir when in contact with surrounding tissue.The wire may comprise material that is a good thermal conductor but thatis an electrical insulator, such as beryllium oxide, hexagonal boronnitride or a polyborazine compound.

The pulse generator 64 is also shown to contain a power module (e.g.,battery) that is used to drive the other circuits within the pulsegenerator. The pulse generator also contains circuits need totransmit/receive data and control signals to/from external devices. Asshown, the communication may be wireless, and the device with which thepulse generator 64 communicates may be a computer that is similarlyconfigured for wireless communication, possibly via a hand-heldprogrammer. For example, the operation(s) to be performed are specifiedby the user in a program in the computer (e.g., selection of energymodalities and their corresponding pulse parameters, or receipt ofmeasurement data from the lead device). Communication between devicespreferably makes use of radio communication within unlicensed ISMfrequency bands. Components of the wireless system in the pulsegenerator 64, computer, and hand-held programmer may comprise asystem-on-chip transciever with an integrated microcontroller; acrystal; associated balun & matching circuitry, and an antenna [DagGRINI. R F Basics, R F for Non-RF Engineers. Texas Instruments, PostOffice Box 655303, Dallas, Tex. 75265, 2006]. The computer can alsocommunicate wirelessly with other sensors that are being used tocharacterize the pathophysiology of the patient, such as data from EEG,ECG, EMG, and electrodermal sensors. The computer may communicatewirelessly with a handheld device that the patient is using as an eventmaker, pain-level indicator, or portable controller/programmer. Thus,the health care provider or patient may select and initiate astimulation protocol using the computer or handheld controller, or mayinitiate a protocol to start the wireless streaming of data measuredusing the lead's electrodes, accelerometers, stress sensors,thermometers, scalp electrodes, ECG electrodes, EMG electrodes,electrodermal sensors, laser Doppler flowmeters, and the like, to thecomputer with which the pulse generator 64 is communicating. Theintegration, analysis and modeling of all such data, and the use of thatdata for controlling stimulation protocols, are described below. Thecomputer may be connected to other computers on the internet, where someof the selection and initiation of protocols, as well as dataacquisition and analysis, may also take place.

Making the patient undergo planned or controlled movements in order togenerate activity in the nerves of the posterior longitudinal ligamentand underlying annulus fibrosus, as well as possibly produce pain, is atype of evoked potential maneuver. Similar maneuvers include thecontrolled or diagnostic vibration of nerves within the posteriorlongitudinal ligament and underlying annulus fibrosus, the controlled ordiagnostic lighting of those nerves, and the controlled or diagnosticheating or cooling of those nerves. The immediate consequence of such adiagnostic stimulus maneuver is then measured using the lead'selectrodes and other measurement devices of the system.

The invention also contemplates the planned or controlled stimulation ofone or more of the lead's electrodes, in order to measure the voltagesthat are evoked at other electrodes of the lead and other measurementdevices of the system (e.g., laser Doppler flowmeter). Any such stimuluswill usually be a single pulse or a series of pulses in the form of astimulus burst, generally of the types that may be combined during atherapeutic stimulus protocol. In the following remainder of thedisclosure, it is assumed that the stimulus pulse or burst of pulsescorrespond to parameter values that would have only reversible effects.For example, if the pulse is electrical, then the amplitude of the pulsewould be limited to values less than about 10 volts, and the timebetween pulses in a burst would correspond to frequencies of less thanabout 10 kHz. The discussion that follows describes how measurement ofthe effects of those pulses or bursts of pulses may be used to selectreversible stimulation modalities and their corresponding parameters,for purposes of therapy.

The neuronal activity evoked by the above-mentioned maneuvers may alsobe measured at scalp electrodes, thereby making the planned stimulationvia the lead's electrodes a type of classical evoked potential (EP)measurement protocol. For example, the investigator initiates thegeneration of one or more sensory stimuli via the pulse generator, suchas a flash of light, a vibration, a pulse of cooling, or an electricalpulse applied to an electrode of the lead. The potentials measured onthe scalp are time-locked relative to the onset of the stimulus. When atransient response EP is measured, the EP waveform ordinarily consistsof a series of peaks and valleys relative to the baseline potential,which are characterized by their amplitudes (positive or negative), aswell as their times of occurrence relative to the stimulus (theirlatencies). The potentials that are so-measured are a mixture of theneural activity of structures involved in both the unconscious andconscious processing of the sensory information, as may be inferred byperforming the EP measurement when the subject is or is notanesthetized, or awake versus asleep. One may use transient response EPdata acquisition equipment that is capable of averaging multiplesuccessive evoked potentials (so as to increase the signal-to-noise ofthe EP data) and also automatically locate peaks or other features inthe evoked potential waveform, such as a P300 peak that corresponds to aconscious evaluation on the part of the patient that the stimulus isinteresting.

Peaks and troughs in the transient response EP may often be identifiedby comparing their properties with those found in normative databases.Artifacts that appear in the EP may also be identified and preferablyeliminated. In general, somatosensory stimuli evoke early corticalcomponents (N25, P60, N80), which are generated in the contralateralprimary somatosensory cortex (S1) related to the processing of thephysical stimulus attributes. About 100 ms after stimulus application,additional cortical regions are activated, such as the secondarysomatosensory cortex (S2), and the posterior parietal and frontalcortices, marked by a parietal P100 and bilateral frontal N140. Astimulus that is applied near the midline of the posterior longitudinalligament may result in an EP that appears on one or the other side ofthe brain, depending on whether the stimulus is applied a little to theleft or to the right of the midline [KNIGHT R T, Scabini D. Anatomicbases of event-related potentials and their relationship to noveltydetection in humans. J Clin Neurophysiol 15(1, 1998):3-13; KECECI H,Degirmenci Y, Atakay S. Habituation and dishabituation of P300. CognBehav Neurol 19(3, 2006):130-134; William R. GOFF. Human average evokedpotentials: procedures for stimulating and recording. Chapter 3, pp.101-156 in: Bioelectric Recording Techniques. Part B.Electroencephalography and Human Brain Potentials (Richard F. Thompsonand Michale M. Patterson, eds). New York: Academic Press, 1974; DavidREGAN. Human Brain Electrophysiology. Evoked potentials and evokedmagnetic fields in science and medicine. New York: Elsevier SciencePublishing Co., 1989, pp. 1-672; Terence W. PICTON, Otavio G. Lins andMichael Scherg. The recording and analysis of event-related potentials.Chapter 1 (pp. 3-73) in Handbook of Neuropsychology, Vol. 10 (F. Bollerand J. Grafman, eds). Amsterdam: Elsevier Science B. V., 1995; MonicaFABIANI, Gabriele Gratton and Michael G. H. Coles. Event RelatedPotentials. Methods, Theory, and Applications. Chapter 3, pp. 53-84 In:John T. Cacioppo, Louis G. Tassinary and Gary G. Berntson (eds).Handbook of Psychophysiology, 2nd Ed. Cambridge: Cambridge UniversityPress, 2000; Steven J. LUCK. An introduction to event-related potentialsand their neural origins. Chapter 1 (pp. 1-50) in: Steven J. LUCK. AnIntroduction to the Event-Related Potential Technique. Cambridge, Mass.:MIT Press, 2005; Todd C. HANDY (ed). Event-related Potentials: A MethodsHandbook. Camridge, Mass.: MIT Press, 2005, pp. 1-380; Steven J LUCK andEmily S Kappenman, eds. Oxford handbook of event-related potentialcomponents. Oxford: Oxford University Press, 2012, pp. 1-626].

An important aspect of the invention is its ability to model, explain,or predict the occurrence of pain as a function of spontaneous (e.g.,ambulatory) or deliberate stimuli that the patient experiences. Giventhat data concerning stimuli and physiological sensors are collected asdescribed above, methods are known in the art that may be used topredict the data related to pain from the other data. The data maycontain all of the variables described above or a subset of them, butshould ordinarily include at least the measurement of pain. Modeling andanalysis of the data are generally performed using the computer withwhich the pulse generator (64 in FIG. 8) is in communication. Themodeling and analysis may be performed using any statistical orartificial intelligence or machine learning or optimization methodsknown in the art, including autoregressive models as well as models thatmake use of principal components, Kalman filters, wavelet transforms,hidden Markov models, artificial neural networks, and/or support vectormachines. In the preferred embodiments of the present invention, supportvector machines are used. A support vector machine (SVM) is analgorithmic approach to the problem of classification within the largercontext of supervised learning [PRESS, W H, Teukolsky, S A, Vetterling,W T, Flannery, B P. Section 16.5. Support Vector Machines. In: NumericalRecipes: The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press, 2007].

In the present context, a training set of data will have been acquiredthat includes whether or not the patient is experiencing pain greaterthan or equal to some specified level, as a function of time. Forexample, using a self-reported pain scale, the specified level may be a“7”, or the equivalent level of pain may have been determined by one ormore of the objective methods that were described above. It isunderstood that the analysis may be repeated using any other numericallevel of pain as a cutoff, so that the analysis contemplates that thepatient may be experiencing an arbitrary level of pain.

The classification of the patient's state at any instant is whether painis being experienced at or above the specified level, and the data usedto make the classification (prediction) consist of the remainingacquired data as a function of time. Thus, the other data generallyinclude a time-series of measured values for each of the other variables(such as electrode voltages, position or mechanical stresses, and/orlaser Doppler flowmeter data, possibly weighted such that older datawithin the time-series have less influence on the analysis), along withdata indicating whether stimulation by any of the modalities is inprogress. The pain datum may be coincident with the most recent timepoint of the other data, or the data may be evaluated over some fixedtime interval prior to the time at which a pain datum is acquired. Inthe former case, the objective is to explain the level of pain basedupon the coincident values of the other data, and in the latter case,the objective is to predict the occurrence of future pain from the otherdata. Thus, the SVM is trained to predict the presence of the specifiedlevel of pain (or greater) from the other coincident data, and/or it istrained to predict from the other data whether the level of pain will beexperienced some specified number of seconds into the future. Byextrapolating the values of the other data into the future, it is alsopossible to use those extrapolated data to predict the future value ofthe patient's pain, using an SVM that is trained with concurrent otherdata, but by training the SVM with other data that had been evaluated attimes prior to acquisition of the pain data, the extrapolation step isavoided. Because the SVM analysis is repeated for all possible painlevels, the analysis collectively endeavors to predict the current orfuture numerical value of pain [Christopher J. C. BURGES. A tutorial onsupport vector machines for pattern recognition. Data Mining andKnowledge Discovery 2(1998), 121-167; J. A. K. SUYKENS, J. Vandewalle,B. De Moor. Optimal Control by Least Squares Support Vector Machines.Neural Networks 14 (2001):23-35; SAPANKEVYCH, N. and Sankar, R. TimeSeries Prediction Using Support Vector Machines: A Survey. IEEEComputational Intelligence Magazine 4(2, 2009): 24-38; Alex J. SMOLA andBernhard Scholkopf. A tutorial on support vector regression. Journal ofStatistics and Computing 14(3, 2004):199-222].

The SVM is trained using as wide a range of data that the patient isexpected to experience during activities of daily living. For example,the data will have been acquired over the course of 24 hours usingambulatory monitoring. Data will also have been acquired under a widerange of deliberate reversible stimulation provocations that might beused therapeutically. Redundancy of the data acquisition conditions willreveal the extent to which the patient's physiology exhibits adaptationor habituation to a given set of provocations, producing differentlevels of pain for a given set of the other data, thereby confoundingthe predictability of the pain.

Simplification of the SVM training is accomplished in part by avoidingthe use of the raw data, but instead by using features that have beenextracted from the raw data. For example, rather than train the SVMusing the spontaneous voltage fluctuations measured from each of theelectrodes of the lead device, one would instead use the total power infrequency bands extracted from those fluctuations, as a function oftime. As another example, instead of using voltages measured from scalpelectrodes, one would instead use measured amplitudes and latencies ofthe corresponding evoked potentials to train the SVM. Simplification ofthe training may also make use of methods that eliminate considerationof variables that are found to have little effect on the prediction ofpain [Felipe ALONSO-Atienza, José Luis Rojo-Álvarez, AlfredoRosado-Muñoz, Juan J. Vinagre, Arcadi García-Alberola, GustavoCamps-Valls. Feature selection using support vector machines andbootstrap methods for ventricular fibrillation detection. Expert Systemswith Applications 39(2012): 1956-1967]. After training the SVM topredict the occurrence of pain from the other data, success of the SVMis tested with data that were not used for the SVM training. If thesuccess rate is not adequate because it produces too many falsepositives or negatives, training and testing of the SVM continues untilthe training is judged to be adequate.

One benefit of training and testing an SVM is that it will provide thephysician with a better sense of which variables are responsible for thepatient's pain and which stimulation modalities and parameter rangeswould most likely effect a reduction in the patient's pain. Thus,analysis of the data concerning the patient's pain, along with the otherdata that may predict that pain, provides diagnostic information to thephysician. With that information, the physician would reduce the timeand effort needed for trial-and-error experimentation with stimulationmodalities and parameter values. The physician may also use thediagnostic data that has been collected for a population of patients, inorder to determine how subsets of patients having similar diagnosticdata respond to different treatment modalities.

However, a greater benefit of training and testing the SVM is that itmay be incorporated into an autonomous or semi-autonomous closed-loopsystem in which the system itself selects stimulation modalities and thecorresponding stimulation parameter values (waveform type, pulseamplitude, frequency, etc.) that may vary according to the patient'scurrently measured state. Such closed-loop systems have been describedas an advance in deep brain stimulation methodology, such thatinherently better therapeutic results can be achieved [STANSLANSKI S,Afshar P, Cong P, Giftakis J, Stypulkowski P, Carlson D, Linde D,Ullestad D, Avestruz A T, Denison T. Design and validation of a fullyimplantable, chronic, closed-loop neuromodulation device with concurrentsensing and stimulation. IEEE Trans Neural Syst Rehabil Eng 20(4,2012):410-421; R. Mark RICHARDSON. Closing the Loop in Neuromodulation:Concurrent Sensing and Stimulation. Neurosurgery 71(2, 2012): N19-N20;AFSHAR P, Khambhati A, Stanslaski S, Carlson D, Jensen R, Linde D, DaniS, Lazarewicz M, Cong P, Giftakis J, Stypulkowski P, Denison T. Atranslational platform for prototyping closed-loop neuromodulationsystems. Front Neural Circuits 6(2013):117, pp. 1-15]. However, suchclosed-loop systems have not been disclosed heretofore for the treatmentof lower back pain.

Using the lead devices and physiological measurements that are disclosedherein, any known feedback or control system method may be used to closethe stimulation loop [Karl Johan ASTROM & Richard M. Murray. FeedbackSystems: An Introduction for Scientists and Engineers. Princeton N.J.:Princeton University Press, 2008; Torkel GLAD and Lennart Ljung. ControlTheory. Multivariable and Nonlinear Methods. New York: Taylor andFrancis, 2000; Zdzislaw BUBNICKI. Modern Control Theory. Berlin:Springer, 2005]. However, the trained and tested SVM may be best suitedto the use of feedforward control methods, as now described [ColemanBROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In: Techniques ofModel-Based Control. Upper Saddle River, N.J.: Prentice Hall PTR, 2002.pp. 221-240].

For any given current values of the pain and other measured values, thesystem provides those other measured values to the SVM as input, whichpredicts the corresponding level of pain. The system also searchesthrough its database of previously recorded data for examples in whichthe patient exhibited similar values of the other measured values anduses those values to predict the pain that had been previously measured.To the extent that the SVM successfully predicts the level of current orpreviously recorded values of pain, the SVM is determined to be usefulunder the patient's current state.

Then, for all such similar examples, the system searches for stimulationmodalities and parameters that had been applied under similar measuredcircumstances, to find the ones that led to the greatest reduction ofpain, in the moments after their application. Initially, the stimulationmodalities and parameters will correspond to the deliberate provocationsof single pulses and bursts of pulses with different stimulationmodalities, which had been made in connection with the measurement ofevoked potentials. The SVM is presented with those data as input, thistime with the variable(s) representing various stimulation modalitiesset to values indicating the presence of their application, as well ashaving a range of possible stimulation parameters. The SVM then predictsthe level of pain under those stimulation parameters. To the extent thatthe SVM can successfully predict the level of previously recorded valuesof pain following stimulation, it is determined that the modality andparameter settings that the SVM predicts to bring about the greatestreduction in pain are therapeutically appropriate, whether or not thosemodality and particular parameter settings had been applied previously.Those stimulation modalities and parameter settings can then be appliedto the patient using the pulse generator. When the measured values ofthe variables subsequently change beyond a de minimis amount, theprocess can be repeated and new stimulation modalities and/or parametersettings are automatically applied to the patient using the pulsegenerator. Therefore, one aspect of the closed-loop embodiment of thepresent invention is that the stimulation modalities and theircorresponding stimulation parameters are generally not set by thephysician even temporarily, and in that sense, the present inventiondiffers fundamentally from neurostimulation treatment for back pain asit is currently practiced.

If no application of stimulation modalities had been performed when thepain and other measured variables were similar to the patient's currentvalues of those variables, the system may then randomly apply singlepulses and bursts of pulses using the different stimulation modalities.The patient's measured response to those random applications will thenbe added to the database of recordings for future reference. Once thedatabase of responses is sufficiently comprehensive, the SVM may beretrained and tested using the updated database of measurements, and thesystem is ready for therapeutic application under a wider range ofconditions. In order that the system be able to promptly select astimulation modality and set of stimulation parameters, the responses todifferent stimulations under different measured states of the patientmay have been preprocessed and indexed offline by the computer housingthe database of measurements. Otherwise, if the search for stimulationmodalities and parameters to find the ones that may lead to the greatestreduction of pain will take a significant amount of computer processingtime, the SVM should be trained to predict into the future the pain thatthe patient will experience, in which the future time is approximatelyequal to the computer's processing time.

The SVM is regularly retrained and tested using data that accumulateslong after the lead device has been implanted into the patient.Therefore, one expects that the ability of the SVM to predict the mosteffective stimulation modality and stimulation parameter values willimprove continuously, and the application of those stimulationmodalities and parameters will eventually lead to a significantreduction of the patient's pain. However, if the pain persists evenafter extended use of the closed-loop system, the physician has theoption of applying irreversible stimulation using any of the modalitiesthat were described above. Selection among the irreversible modalitiesmay be based upon a determination that one of the reversible modalitieshad the greatest effect in reducing the patient's pain, howeverincomplete that reduction was.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. A method of treating discogenic lumbar backpain in a patient comprising: positioning a plurality of electrodeswithin an anterior epidural space of the patient to a position adjacentto a posterior longitudinal ligament and/or a posterior annulusfibrosus; generating one or more electrical impulses with a pulsegenerator; and transmitting the electrical impulses through saidelectrodes to one or more nerves in said posterior longitudinal ligamentand/or said posterior annulus fibrosus; wherein the electrical impulsesare sufficient to cause one or more sympathetic nerves in the posteriorlongitudinal ligament and/or in the posterior annulus fibrosus toinhibit an initiation and/or a transmission of an action potential inone or more nociceptive nerves in the posterior longitudinal ligamentand/or in the posterior annulus fibrosus; wherein the electricalimpulses promote the release of one or more molecules of norepinephrinefrom the sympathetic nerves, thereby promoting a binding of thenorepinephrine molecules to an alpha-2 adrenoreceptor in the nociceptivenerves, whereby the initiation and/or the transmission of the actionpotential in the nociceptive nerves is inhibited; and wherein theelectrical impulses at least partially relieve the pain withoutproducing irreversible damage in any tissue of the patient.
 2. Themethod of claim 1 wherein a sympathetic tone in the patient and a levelof pain in the patient are measured, and wherein said tone and saidlevel are found to be negatively correlated prior to the transmittingstep.
 3. The method of claim 1 wherein the electrical impulses aretransmitted preferentially to sympathetic nerves in a superficial layerof the posterior longitudinal ligament, in a deep layer of the posteriorlongitudinal ligament, or in a superficial layer of the posteriorannulus fibrosus.
 4. A method of treating discogenic lumbar back pain ina patient comprising: positioning a plurality of electrodes within ananterior epidural space of the patient to a position adjacent to aposterior longitudinal ligament and/or a posterior annulus fibrosus;generating one or more electrical impulses with a pulse generator; andtransmitting the electrical impulses through said electrodes to one ormore nerves in said posterior longitudinal ligament and/or saidposterior annulus fibrosus; wherein the electrical impulses aresufficient to inhibit one or more sympathetic nerves in the posteriorlongitudinal ligament and/or in the posterior annulus fibrosus frompromoting an initiation and/or a transmission of an action potential inone or more nociceptive nerves in the posterior longitudinal ligamentand/or in the posterior annulus fibrosus; wherein the electricalimpulses inhibit the release of one or more molecules of norepinephrinefrom the sympathetic nerves, thereby inhibiting a binding of thenorepinephrine molecules to an alpha-1 adrenoreceptor in the nociceptivenerves, whereby the initiation and/or the transmission of the actionpotential in the nociceptive nerves is inhibited; and wherein theelectrical impulses at least partially relieve the pain withoutproducing irreversible damage in any tissue of the patient.
 5. Themethod of claim 4 wherein a sympathetic tone in the patient and a levelof pain in the patient are measured, wherein said tone and said levelare found to be positively correlated prior to the transmitting step. 6.The method of claim 4 wherein the electrical impulses are transmittedpreferentially to sympathetic nerves in a superficial layer of theposterior longitudinal ligament, in a deep layer of the posteriorlongitudinal ligament, or in a superficial layer of the posteriorannulus fibrosus.
 7. A device for treating discogenic lumbar back painin a patient comprising: a plurality of electrodes that is coupled to anelectrical pulse generator; wherein the plurality of electrodes isconfigured to be positioned within an anterior epidural space of thepatient at a position adjacent to a posterior longitudinal ligamentand/or a posterior annulus fibrosus; wherein the pulse generator isconfigured to transmit electrical impulses through said electrodes to atleast partially relieve the pain without producing irreversible damagein any tissue of the patient; and wherein the electrical impulsesexhibit at least two alternate, selectable waveform configurations,comprising at least a Waveform Configuration A and an alternate WaveformConfiguration B; wherein when Waveform Configuration A is selected, theelectrical impulses cause one or more sympathetic nerves in theposterior longitudinal ligament and/or in the posterior annulus fibrosusto inhibit an initiation and/or a transmission of an action potential inone or more nociceptive nerves in the posterior longitudinal ligamentand/or in the posterior annulus fibrosus; wherein when WaveformConfiguration A is selected, the electrical impulses promote the releaseof one or more molecules of norepinephrine from the sympathetic nerves,thereby promoting a binding of the norepinephrine molecules to analpha-2 adrenoreceptor in the nociceptive nerves, whereby the initiationand/or the transmission of the action potential in the nociceptivenerves is inhibited; and wherein when Waveform Configuration B isselected, the electrical impulses inhibit one or more sympathetic nervesin the posterior longitudinal ligament and/or in the posterior annulusfibrosus from promoting an initiation and/or a transmission of an actionpotential in one or more nociceptive nerves in the posteriorlongitudinal ligament and/or in the posterior annulus fibrosus; whereinwhen Waveform Configuration B is selected, the electrical impulsesinhibit the release of one or more molecules of norepinephrine from thesympathetic nerves, thereby inhibiting a binding of the norepinephrinemolecules to an alpha-1 adrenoreceptor in the nociceptive nerves,whereby the initiation and/or the transmission of the action potentialin the nociceptive nerves is inhibited.
 8. The device of claim 7 furthercomprising a flexible and/or elastic electrically insulating materialhaving a first side and an opposing second side, wherein said electrodesare attached to said insulating material, and wherein said electrodesare disposed along the first side of said electrically insulatingmaterial.
 9. The device of claim 8, wherein the electrical impulses aretransmitted through said electrodes substantially in one direction. 10.The device of claim 9, wherein the electrodes are disposed substantiallylinearly along the electrically insulating material, and wherein theelectrodes and the insulating material are configured to be insertedinto the patient percutaneously through a neural foramen.
 11. The deviceof claim 10 further comprising fins, wherein said fins are joined to theinsulating material.
 12. The device of claim 8 wherein the plurality ofelectrodes is disposed nonlinearly or linearly along the first side ofthe electrically insulating material, and wherein a length, and/or awidth, and/or a perimeter of said insulating material is configured tofit within a selected dimension and/or a selected surface area of one ormore lumbar discs of the patient and/or to fit within a selecteddimension and/or a selected surface area of an intervening vertebralbodies of said discs of the patient, and/or to fit within a selecteddistance between two adjacent ipsilateral nerve roots of the patient.13. The device of claim 12 wherein the length, and/or width, and/orperimeter of said insulating material is configured to fit within theselected dimension and/or surface area of a single intervertebral discof the patient.
 14. The device of claim 13 wherein the length, and/orwidth, and/or perimeter of said insulating material is configured to fitwithin the selected dimension and/or surface area of two or moreintervertebral discs of the patient and/or of the selected dimensionand/or surface area of the intervening vertebral bodies of said discs.15. The device of claim 8 wherein the insulating material is connectedto one or more anchoring tabs that are configured for the attachment ofsaid tabs to a tissue of the patient.
 16. The device of claim 7 whereinthe plurality of electrodes is coupled to the electrical pulse generatorwith electrically conducting wires.
 17. The device of claim 7 whereinthe electrical pulse generator is configured to be implanted within thepatient.
 18. The device of claim 7 wherein power is supplied to theelectrical pulse generator by batteries.
 19. The device of claim 7wherein power is supplied to the electrical pulse generator by areceiver that is inductively coupled by a receiving coil to aphysically-unattached external transmitter.
 20. The device of claim 7wherein the electrical impulses comprise rectangular, biphasic, chargebalanced pulses of adjustable rate, adjustable duration and adjustableamplitude for each electrode among the plurality of electrodes.
 21. Thedevice of claim 7 wherein each electrode among the plurality ofelectrodes is configured to be disconnectable from the pulse generator.22. The device of claim 7 wherein an adjustment of each electrode'selectrical impulse rate, duration, amplitude and anode/cathodeconfiguration, and of each electrode's connection or disconnection tothe pulse generator, is made by the pulse generator using controlsignals that are transmitted to the pulse generator by a programmer. 23.The device of claim 22 wherein the transmission of the control signalsis to a receiver of the pulse generator, said receiver being inductivelycoupled by a receiving coil to a physically unattached externaltransmitter of the programmer.
 24. The device of claim 7 wherein theelectrical impulses comprise pulses having a frequency of between about0.01 Hz and 10,000 Hz.
 25. The device of claim 7 wherein the electricalimpulses comprise pulses having a frequency of between about 20 Hz and120 Hz.
 26. The device of claim 7 wherein the electrical impulsescomprise pulses having a width of between about 100 and 400microseconds.
 27. The device of claim 7 wherein the electrical impulsescomprise pulses having an amplitude of between about 0.001 and 10 volts.28. The device according to claim 7, and further comprising a trocar, ora guide wire, or a stylet, or an introducer cannula, or an obturator, ora lead blank; wherein the trocar, or the guide wire, or the stylet, orthe introducer cannula, or the obturator, or the lead blank isconfigured for the placement into the patient of the device according toclaim 7.